JANUARY 2017 Volume 29 Number 1

Packaging Trends 2017 From blister packaging to patient-centred fill/finish operations

SOLVING PHARMA’S POST-BREXIT PUZZLE

FORMULATION PEER-REVIEWED Oligonucleotide Therapeutics Out-of-Trend Evaluation

January 2017 Pharmaceutical Technology Europe is the authoritative Advancing Development & Manufacturing source of peer-reviewed research and expert analyses for scientists, engineers, and managers engaged in process PharmTech.com development, manufacturing, formulation and drug delivery, API synthesis, analytical technology and testing, packaging, IT, outsourcing, and regulatory compliance Cover: A-R-T & Sashkin/ in the pharmaceutical and biotechnology industries. Shutterstock.com Art direction: Dan Ward

2428 16 40

PharmTech.com

Features Peer-Reviewed FOCUS: PACKAGING TRENDS 32 A Statistical Decision System 16 Blister Packaging Moves Forward for Out-of-Trend Evaluation Advances in materials and equipment The authors present a set of statistical for pharmaceutical blister packaging decision rules based on linear regression protect quality and enhance . models that can be implemented in an automated trend system to assist stability studies. 20 Packaging’s Flexible, Patient-Centred Future Primary packaging and design reflects a move to patient-friendly formulations and delivery systems, and more agile manufacturing processes. Regulars and Columns

22 New Packaging Solutions on 6 GMP/GDP Inspections Display at Pharmapack 2017 The GMP/GDP Inspection Landscape–Part I: Data Manufacturers will display a variety of unique packaging solutions during Pharmapack Europe 2017. 12 European Regulatory Watch The Evolving Role of HTA Bodies Sparks Scrutiny 2017 EUROPEAN BIO/PHARMA OUTLOOK 24 Solving the Post-Brexit Puzzle 14 Outsourcing Review As Europe’s bio/pharma market learns that The Tide Stays High breaking up is hard to do, it must address productivity, regulatory, and drug pricing challenges. 46 Ad Index

FORMULATION: OLIGONUCLEOTIDES 47 Pharmapack Exhibitor Profiles 28 Characterization and Impurity Analysis of Oligonucleotide Therapeutics 50 Ask the Expert Analytical technologies play a key role in the characteri- Staffing and Preparation for Audits zation and quantitation of oligonucleotide therapeutics.

SINGLE-USE MANUFACTURING 40 Validating a Method for Point-of-Use Leak Testing of Single-Use Assemblies The authors describe the development and validation PTE’s of a highly sensitive point-of-use pressure decay test. Join community Join the Pharmaceutical Technology Europe group on LinkedIn™* PROCESS OPERATIONS and start discussing the issues that matter to you with your peers. 44 Defining Quality: Go to PharmTech.com/linkedin Joining the Quality Lab and the Plant Floor As pharmaceutical quality metrics evolve, * The linkedIn logo is a registered trademark of LinkedIn Corporation and its affi liates in the United States and/or other countries they will need to incorporate more of the principles of operational excellence, says consultant Prabir Basu.

Pharmaceutical Technology Europe JANUARY 2017 3 EDITORIAL ADVISORY BOARD

PharmTech Europe Contributing Editor Editor Cynthia A. Challener, PhD Reinhard Baumfalk Luigi G. Martini Adeline Siew, PhD Global Correspondent Vice-President, R&D Chair of Pharmaceutical [email protected] Sean Milmo Instrumentation & Control Innovation PharmTech Group (Europe, [email protected]) Sartorius AG King’s College London Editorial Director Art Director Rafael Beerbohm Rita Peters Dan Ward Thomas Menzel [email protected] Director of Quality Systems Menzel Fluid Solutions AG Publisher Boehringer Ingelheim GmbH Senior Editor Michael Tracey Jim Miller Agnes Shanley [email protected] Phil Borman [email protected] President,PharmSource Sales Manager Manager, GlaxoSmithKline Information Services Managing Editor Linda Hewitt Evonne Brennan Susan Haigney Tel. +44 (0) 151 353 3520 Colin Minchom [email protected] [email protected] European Technical Product Senior Director Manufacturing Editor Senior Sales Executive Manager, Pharmaceutical Pharmaceutical Sciences Jennifer Markarian Stephen Cleland Division, IMCD Ireland [email protected] Shire Pharmaceuticals Tel. +44 (0) 151 353 3647 Rory Budihandojo Science Editor [email protected] Clifford S. Mintz Randi Hernandez Director, Quality and EHS Audit President and Founder Sales Operations Executive [email protected] Boehringer-Ingelheim Barbara Williams BioInsights Community Editor [email protected] Christopher Burgess Tim Peterson Caroline Hroncich Managing Director [email protected] Transdermal Product Burgess Analytical Consultancy Development Leader, Drug Published by VP & Managing Director, Pharm/ Ryan F. Donnelly Delivery Systems Division, 3M UBM Science Group Professor Hinderton Point Dave Esola John Pritchard Lloyd Drive Queens University Belfast VP & Managing Director, CBI/IVT Technical Director Cheshire Oaks Tim Freeman Cheshire CH65 9HQ, United Kingdom Johanna Morse Philips Respironics Tel. +44 151 353 3500 VP & Managing Director, Managing Director Thomas Rades Fax +44 151 353 3601 Veterinary Group Freeman Technology Becky Turner Chapman Professor, Research Chair in UBM Americas: Filipe Gaspar Formulation Desgin and Drug De- Chief Executive Officer VP, Marketing & Audience Scott Schulman Development Vice-President, R&D livery, University of Copenhagen Joy Puzzo Hovione Chief Operating Officer Rodolfo Romañach Brian Field VP, Media Operations Sharon Grimster Francis Heid Professor of Chemistry Head of Legal ReNeuron University of Puerto Rico, Michael Bernstein Director, Human Resources Jamie Scott Durling Anne Marie Healy Puerto Rico EVP & Senior Managing Director, UBM PLC: Professor in Pharmaceutics and Siegfried Schmitt Life Sciences Group Chief Executive Officer Tom Ehardt Pharmaceutical Technology Principal Consultant Tim Cobbold Trinity College Dublin, Ireland Senior VP, Finance PAREXEL Group Operations Director Tom Mahon Andrew Crow Deirdre Hurley Stane Srcic EVP & Managing Director, UBM Senior Director, Plant Chief Financial Officer Professor Medica Marina Wyatt Helsinn Birex Georgiann DeCenzo University of Ljubljana, Slovenia Chairman Pharmaceuticals Ltd. EVP, Strategy & Business Griet Van Vaerenbergh Dame Helen Alexander Development Makarand Jawadekar GEA Process Engineering Mike Alic Independent Consultant Benoît Verjans Henrik Johanning CEO CEO, Senior Consultant, Arlenda Editorial: All submissions will be handled with reasonable care, but the publisher assumes no responsibility for safety of Genau & More A/S artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but the publisher cannot accept Tony Wright responsibility for the accuracy of information supplied herein or for any opinion expressed. Marina Levina Subscriptions: Managing Director Pharmaceutical Technology Europe is free to qualified subscribers in Europe. Product Owner-OSD, TTC- To apply for a free subscription, or to change your name or address, go to PharmTech.com, click on Subscribe, & follow Exelsius the prompts. Tablets Technology Cell, GMS To cancel your subscription or to order back issues, please email your request to [email protected], putting PTE in the subject line. GlaxoSmithKline Please quote your subscription number if you have it. Roberto Margarita List Rental: Contact Sarah Darcy; Tel. +44 1244 629 326 Fax +44 1244 659 321 Reprints: Reprints of all articles in this issue and past issues are available (500 minimum). Platform Director Contact Brian Kolb at Wright’s Media, 2407 Timberloch Place, The Woodlands, TX 77380. Telephone: 877-652-5295 ext. 121. Email: [email protected]. Corden Pharma

Copyright 2017. Advanstar Communications (UK) Ltd. All rights reserved. No part of this publication may be reproduced in any material form (including photocopying or storing it in any medium by electronic means and whether or not transiently or incidentally to some other use of this publication) without the written permission of the copyright owner except in accordance with the provisions of the Copyright, Designs & Above is a partial list of the Pharmaceutical Technology brand editorial advisory mem- Patents Act (UK) 1988 or under the terms of a licence issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP, UK. bers. The full board, which includes advisory members of Pharmaceutical Technology North America, can be found online at www.PharmTech.com/pharmtech-editorial- Applications for the copyright owner’s permission to reproduce any part advisory-board. Pharmaceutical Technology publishes contributed technical articles of this publication should be forwarded in writing to Permissions Dept, Honeycomb West, Chester Business Park, Wrexham Road, Chester, CH4 9QH. that undergo a rigorous, double-blind peer-review process involving members of our Warning: The doing of an unauthorized act in relation to a copyright work distinguished Editorial Advisory Board. Manuscripts for editorial consideration should may result in both a civil claim for damages and criminal prosecution. 10% Post Consumer be sent directly to Susan Haigney, managing editor, [email protected]. Waste

4 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com IF YOU NEED ASEPTIC PACKAGING, BLOW-FILL-SEAL IS THE SOLUTION.

Would you like to fi ll your liquid or semisolid pharmaceuticals in a more reliable, more economical, and more user-friendly way than is possible with conventional methods? Then it's high time for blow-fi ll-seal technology from Rommelag. Our bottelpack systems enable aseptic fi lling in application-optimized plastic , which are directly produced, fi lled, and sealed by the system. These shatterproof containers are free of contamination and correspond to the fi lling quantities that you and your clients need. More information on blow-fill-seal technology and your personal contact partner can be found on our website. www.rommelag.com .de medienformer GMP/GDP INSPECTIONS The GMP/GDP Inspection Landscape— Part I: Data

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has conducted an annual survey of GMP/GDP inspections at sites and affiliates among its member companies from 2003 until the present time. This article describes findings of the EFPIA annual survey of site inspections among its member companies.

Stephan Rönninger* ood manufacturing practice (GMP) inspections some regions, inspections of API manufacturers are is director, External Affairs, Gare fundamental for ensuring that medicinal also mandatory. Furthermore, relevant regulations Amgen (Europe) GmbH; products are produced to the high standards for quality systems (3) require companies to have Johanna Berberich is required for patient safety. The European Federation an independent auditing scheme of their sites, senior manager, Quality of Pharmaceutical Industries and Associations contractors, and suppliers. Recent emerging Audits & Inspections, (EFPIA) represents research-based pharmaceutical regulations require regulatory authorities to inspect Bayer; Véronique companies in Europe. For reasons of transparency, manufacturers in the countries where the medicines Davoust is senior EFPIA conducts an annual survey of inspections and APIs are produced. manager, Global Quality among its member companies. The data generated Intelligence, Pfizer; Peter demonstrate the workload, use of resources, and the Objective, scope, and Kitz is vice-president, outcome of inspection practices for oversight of GMP definition of the EFPIA survey Global Pharmaceutical and good distribution practice (GDP) by domestic and The objective of the annual survey is to provide Quality, Bristol-Myers foreign regulatory authorities. awareness of global health authority inspection Squibb; and Andreas Member companies are confronted with more activity, focusing on duplicate inspections as a Pfenninger is member inspections of their manufacturing sites by authorities means of determining the value to the patient while of the management team, from other countries (i.e., foreign inspections). The controlling risk. Through the annual survey, EFPIA Registration, Production, purpose of this data collection is to create awareness aims to encourage regulatory authorities to focus Quality, Environmental and develop potential opportunities to redirect their resources on activities that pose higher risks to Protection, Interpharma. resources toward better site coverage and, therefore, patient safety and to drive a collaborative approach protection of the patients. Part I of this article reports, among health authorities in inspection practice and *To whom all for the first time, the results of the annual inspections sharing of inspection outcomes. EFPIA recognizes correspondence should be survey. Part II will look at additional challenges and that convergence in activities between regulators addressed. opportunities for improving inspection efficiency (1). is essential to effectively evaluate commercial manufacturing capabilities. Legal background The EFPIA member companies reported inspections According to the International Council for at companies of research-based manufacturers. The Harmonization of Technical Requirements for Human numbers should be seen as a snapshot. Aspects of Use (ICH), inspections of a firm’s manufacturing the survey are as follows: operation are essential to evaluate commercial t Regulatory GMP/GDP inspections conducted at manufacturing capability, adequacy of production manufacturing sites and affiliates, inside and and control procedures, suitability of equipment outside the regulatory authority’s own borders, and facilities, and effectiveness of the quality including related International Organization of management system in assuring the overall state of Standardization (ISO) certifications (e.g., for control. Notably, pre-approval inspections include combination products/medical devices) are the added evaluation of authenticity of submitted included in the data. data and link to dossier (2). Inspections of a firm’s t Only companies that own facilities are reported, manufacturing operations assess GMP and GDP as inspections of contract manufacturers might be compliance and are legally required for drug counted twice.

(medicinal) products in most countries worldwide. In t Sites that manufacture both human and veterinary Images Source/Getty Image image) (Spotlight

6 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com VIABLE AIR MONITORING IS JUST ONETOUCH AWAY

SMASMA OONETOUCHNETOUUCCHH ® ICSICS A FULLYFULLYU Y INTINTEGRATEDEGRATED PPLCLC CONTROLLECONTROLLEDD VVIAVIABLEBLE MMONITORINGONITTORINNG SYSTEM FEATURESFEATTURES PRECISE AND CALIBRATED AIR SAMPLING TO EACH SMA ATRIUM REAL TIME MONITORING AND CONTROL OF ALL SAMPLE PARAMETERS IMMEDIATE ALARMING FUNCTION ON ANY SAMPLING LOCATION FULL INTEGRATION OF FACILITY MAPS AND FLOOR PLANS LEARN MORE AT WWW.STERILE.COM

VELTEK ASSOCIATES ,INC M EgLLLgHgSTERILE SMAuSTERILE.COM GMP/GDP Inspections

Figure 1: Regional split of foreign inspections in 2015; inspector days and 4456 domestic inspector days. It Group 1 >60 inspections; Group 2 >20 inspections. should be noted that these days were spent by regulators only; industry resources are not included in the figures.

USA* Also, these days do not include resources used for - 100 EU* South Korea* based inspections or inspections where no inspector Brazil** Turkey** days had been reported. Less than 10% of the inspections Kenya 80 Japan* were reported as unannounced. Whether announced or Mexico** China unannounced, there was a high level of compliance (more Belarus*** 60 Canada* than 95% of the inspections had positive outcomes, with Colombia Nigeria no regulatory action required). Kazakhstan*** Uganda 40 Soudi Arabia Chinese Taipei* WHO Inspectorates performing foreign inspections Australia* 20 Russia Over the past 12 years, 64 countries have performed Iran** Malaisia* foreign inspections. In 2015, 34 countries performed Libya Number of foreign inspections reported Number of foreign foreign inspections, compared with 40 in 2014 and 31 in 0 Sudan & 7 countries wit 2015 Ivory Coast 1 foreign inspection 2013. The survey results showed the number of foreign *PIC/S member **PIC/S accession ***PIC/S pre-accession inspections per country in 2015 (see Figure 1). Group 1 is formed by countries performing more than 60 foreign inspections; Group 2 is for countries performing more than 20 and less than 60 foreign inspections. In addition to Figure 2: Product types and operations inspected in foreign inspections. those shown in Figure 1, there were also seven countries DP is drug product, DP/S is sterile drug product, API/B is biologic API, where one foreign inspection was made. MedDev is medical devices. The data show that countries in Group 1—the United States and the European Union (where all EU countries are 100% counted as one inspectorate)—perform approximately MedDev twice the number of foreign inspections compared with 6 80% 7 countries in Group 2. A trend analysis of survey data from 15 8 7 Vaccines 14 5 2011 to 2015 revealed: 12 8 7 12 8 Others t A downward trend in the number of foreign inspections 60% 22 3 being performed annually by Group 1 and Group 2 10 API/B

[%] 14 16 19 countries from 2011 to 2015 with some exceptions. 40% 23 14 API t An upward trend in the number of foreign inspections 30 4 being performed annually by other countries (e.g., China 20% DP/S 33 18 42 19 16 performed five foreign inspections in 2011 compared

Number of foreign inspections Number of foreign 7 DP with 16 in 2015; Belarus performed three foreign 0% inspections in 2011 compared with 12 in 2015). US EU SouthKorea Brazil Turkey Kenya Japan Analysis of foreign inspection activity between the ICH founding members of the US, EU, and Japan in 2015 revealed the following: t The US performed 62 foreign inspections in the EU, products are included in the scope of this survey. Other compared with 104 inspections in the previous year. It inspection types (e.g., on pharmacovigilance aspects performed no inspections in Japan in 2015, compared [GPvP], inspection on narcotics, and environmental with one inspection in 2014. safety) had been reported in some cases, but not t The EU performed 35 foreign inspections in the US, assessed. compared with 36 in 2014; it conducted no inspections t Sites manufacturing exclusively veterinary products are in Japan, compared with one inspection in 2014. not reported. t Japan conducted 12 inspections in Europe in 2015, In addition to the data collection, there are specific compared with 23 in 2014; it performed 10 inspections questions concerning inspection activities that are in the US in 2015, versus 19 inspections in 2014. adapted each year to reflect areas of particular interest There were significantly fewer inspections from the to EFPIA. The definitions used in the survey are available US in Europe (approximately 40%) and from Japan in the online (listed online in Table I). EU (approximately 48%). Similar reductions had been reported in the 2014 data. Data assessment Over the span of the survey so far (2003 to 2015), Number of on-site inspections at a site data have been collected from approximately 660 The maximum number of inspections at a single site manufacturing sites annually. Conducting and receiving within one year has been reported to be 15, including inspections involve considerable regulator and industry seven foreign inspections. The same workload for foreign resources. There were 486 foreign inspections and inspections had been reported by five sites. Overall,

693 domestic inspections, which required 3951 foreign 52 sites received more than four inspections in 2015, Figures are courtesy of the authors

8 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com GMP/GDP Inspections

570 sites report having between one to the scope of the distribution license. A four inspections in 2015, and 118 did not significant number of new regulations receive any inspections in 2015. Although and guidelines (4–7) were published in the number of sites with no inspection recent years aiming at better control of is decreasing, indicating better overall distribution channels to prevent entry coverage, there are still sites that are not of falsified products in the legal supply inspected. This observation might suggest chain. Inspections of GDP compliance are, that resources could be better balanced. therefore, deemed to be important. They The survey asked for specific data from can be performed at a manufacturing sites receiving multiple inspections, with site and/or at an affiliate of the company the aim of addressing the question: “Are in the country of destination or at a hub. multiple inspections driven by risks?” It was The survey shows that more of these noted that one manufacturing site can have inspections are performed each year. several manufacturing licenses, thus there In the 2015 survey, 203 inspections were can be a need for several inspections at reported to include GDP in their scope: THE the same geographical location. However, t 91% were domestic inspections—81% there was no clear indication that these at affiliates and 19% at manufacturing SCIENCE OF multiple inspections were always driven by sites; 2% of the inspections covered APIs risk. The data also confirmed that there is or API/sterile and 98% covered finished always intensive domestic oversight. products; none of these inspections COMPLIANCE reported a follow-up with interruption of Inspections at a manufacturing site supply In general, the inspections cover drug t 9% foreign inspections were products (64%, including 18% sterile reported—58% of these inspections operations), API (20%, including 10% had been performed at manufacturing biotech API sites), vaccines manufacturers sites; 42% of these inspections at (8%), others (5%), and medical devices affiliates (15% of these included an ISO (3%). The majority of foreign inspections certification). target the drug product (see Figure 2). The survey results confirm the split of Inspections at affiliates product types inspected remains constant Out of the 22 companies surveyed in 2015, among the different inspectorates with the 16 reported inspections at affiliates. The exception of Japan. The authors believe majority of inspections were conducted this could be a result of the specific according to distribution licence. Other mutual recognition agreement (MRA) topics covered are GMPs (e.g., supply between Japan and Europe. chain verification by a responsible person, repackaging, relabeling), other The World Leader in UV, Operations inspected GxP processes (e.g., pharmacovigilance), 9LVLEOHDQG1,5&HUWLĆHG Of reported inspections, 85% were GMP and ISO certifications. There were 309 Reference Materials related, 4% were GDP related, 3% covered inspections at affiliates; 96% were domestic ISO certification, and 8% were related to inspections (performed by inspectorates ISO/IEC 17025 other GxP operations. The data show that: from 99 countries), and 4% were foreign Calibration t 79% of domestic inspections concerned inspections: GMP compared with 94% of foreign t 83% of all inspections had no follow-up NIST Traceable inspections t 10% of all inspections had follow-up t 5% of domestic inspections examined without interruption of supply ISO Guide 34 Reference GDP compared with 2% of foreign t 6% of all inspections had follow-up with Material Producer inspections interruption of supply (e.g., distribution t 11% of domestic inspections examined affected, import delay, delivery to Lifetime Guarantee other GxP compared with 4% of foreign customers affected) inspections. t 1% of all inspections had no outcome Fast Recalibration Foreign inspections focused largely on reported/outcome pending. Service GMP processes. Inspection of distribution The majority of inspections at affiliates licenses was performed mostly by the named the GDP distribution license as the domestic regulatory authorities. primary scope of the inspection and drug product as the product type inspected. [email protected] 0659 Considerations of GDP inspections www.starna.com For the purpose of the survey, a GDP Different forms of inspection

REFERENCE MATERIALS inspection is defined as an inspection The survey analyzed the different forms +44(0) 20 8501 5550 4001 that covers systems and processes within of inspections. In 2015, there were 160

Pharmaceutical Technology Europe JANUARY 2017 9 GMP/GDP Inspections

Figure 3: Assessment of outcome of inspections at manufacturing sites 2015. Acknowledgements Data were evaluated by the following members of the EFPIA 100% GMP network reporting to the Technical Development Expert 81.5% 79.9% Group (TDEG): Stephan Rönninger, 80% Amgen (moderator); Johanna Berberich, Bayer; Véronique 60% Davoust, Pfizer; Peter Kitz, Bristol- Myers Squibb; and Andreas N: No follow up Pfenninger, Interpharma. Support 40% needed was provided by Gerd Fischer, F: Follow-up without Boehringer Ingelheim. The authors 20.0% 18.5% interruption of supply Percent of all inspections Percent 20% thank Michele Hunter for technical W: Follow-up with writing. 0.0% 0.1% interruption of supply In addition, the authors thank the 0% companies that provided input to the Foreign Domestic survey in 2015 and before: AbbVie, Almirall, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Biogen, Bristol-Myers Squibb, Eli inspections flagged as pre-approval in 2015. These inspections were Lilly and Company, Grünenthal inspections (PAI) of manufacturing conducted by China, Chinese Taipei, GmbH, GlaxoSmithKline, Johnson sites (95 were foreign and 65 were Germany, Japan, South Korea, Syria, & Johnson, Merck (MSD), Merck domestic inspections). and US FDA. Inspected companies felt Serono, Novartis, Novo Nordisk, Two joint inspections were a need to involve a lot of resources Pfizer, Roche, Sanofi, Servier, Takeda, reported in 2015, which were in fact, due to requests for specific inspection and UCB. two inspections running in parallel formats and questionnaires. This at the same time and were thus issue was compounded by the fact References “concomitant” inspections rather that institutionalized formats such 1. S. Rönninger et al., The GMP/GDP than joint inspections: one inspection as the PIC/S site master file were not Inspections Landscape—Part II: in the US from the and Drug accepted by the different regulators. Opportunities and Considerations, Administration (FDA) and EU, and one Pharm. Tech. Europe, 2017, in press. inspection in Australia by Australia’s Assessment of the 2. ICH, Quality Implementation Working Therapeutic Goods Administration outcome of inspections Group on Q8, Q9, and Q10: Training (TGA) and US FDA. Data on compliance following Material, www.ich.org/products/ In the past, the industry has inspections are shown in Figure 3. guidelines/quality/training-pro- described positive and negative The data indicate that domestic and gramme-for-q8q9q10/presentations. views of joint inspections, with some foreign inspections lead to similar html, accessed July 2016. companies questioning the benefits outcomes. 3. ICH, ICH Harmonized Tripartite and reporting that it feels like two Guideline, Pharmaceutical Quality different inspections at the same Conclusion System Q10, step 4 version (June time. From the regulators’ point Inspections are essential to 2008). of view, there is an open question evaluate commercial manufacturing 4. Amending Directive 2001/83/EC on if joint inspections will continue capability, adequacy of production the Community Code Relating to to be organized. Joint inspection and control procedures, suitability Medicinal Products for Human Use, pilot programmes were initiated by of equipment and facilities, and Falsified Medicines Directive (1 Apr. US FDA. Later, US FDA joined the effectiveness of the quality 2011). Pharmaceutical Inspection Convention management system in assuring 5. Good Distribution Practice of and Pharmaceutical Inspection the overall state of control and can Co-operation Scheme (PIC/S), shifting include the evaluation of authenticity Medicinal Products for Human Use, the exchange toward mutual reliance of submitted data in a registration Guideline 2013/C 343/01 (5 Nov. 2013). on inspection data from partner dossier. The results of the survey 6. Principles of Good Distribution inspectorates. The PIC/S Joint Audit based on the 2015 inspection data Practice of Active Substances for Programme could still be used for and trends since 2003 demonstrate Medicinal Products for Human Use, alignment and training purposes. dublication, workload, use of 2015/C 95/01 (19 Mar. 2015). resources, and the outcome of 7. EC, Good Distribution Practice for Paper-based foreign inspections inspection practices for oversight Medicinal Products for Human Twenty-four paper-based inspections of GMP and GDP inspections and Use, Questions and Answers, were reported as foreign inspections cerifications. Ares(2014)968163 (28 Mar. 2014). PTE

10 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com storgaarddesign.com Do you need to cut API manufacturing costs?

Improved protein solubility and titres Example study: Production of a challenging antibody with the VB expression vector platform fragment in HCD E. coli fermentation

Low Intermediate Innovative solutions are required for the development 2.5 plasmid copy number plasmid copy number

of cost-effective API production processes in the ) 2.0 Soluble g/l highly competitive pharmaceutical industry. Vectron ( 1.5 Insoluble provides next-generation upstream technologies for 1.0

increased protein titres and solubility in E. coli and scFv phOx 0.5 other bacteria. 0 0.1 0.5 3.0 0.1 0.5 3.0 Contact us for feasibility studies for your protein. Inducer concentration (m-toluic acid) in mM

For more information, visit: www.vectronbiosolutions.com Sean Milmo is a freelance writer based in Essex, UK, [email protected].

The Evolving Role of HTA Bodies Sparks Scrutiny

Political pressure to closely examine the relationship between drug prices, R&D, and production costs has increased, but how involved should HTA bodies be in assessing cost effectiveness and reimbursements?

overnments in Europe are increasingly looking to health “At present, HTA bodies do not hold the knowledge and Gtechnology assessment (HTA) organizations to help them understanding to provide scientific advice in respect of gain a tighter grip on expenditure within the region’s pre- production processes, in particular bio-manufacturing dominantly state-funded healthcare services. As a result, the processes,” a spokesman for the European Federation of pharmaceutical industry is having to deal with a rising number Pharmaceutical Industries and Associations (EFPIA) told of HTA bodies. Currently there are more than 50 national and Pharmaceutical Technology Europe. He pointed out that regional HTA organizations in the 28-member states of the the London-based European Medicines Agency (EMA) and European Union and in non-EU states such as Norway and national licensing authorities have specialist knowledge of Switzerland. Their main task is to assess the clinical effec- how production processes can affect the quality, safety, tiveness of a new medicine in relation to similar products on and efficacy of medicines. “We would consider this kind of the market so that an HTA can help in the fixing of the drug’s expertise [in HTA bodies] as unnecessary to assess the clinical price and of the level of reimbursement at the national level. benefit of a new medical technology, including new medicines,” he continued. “It would be a superfluous duplication of A broadening scope of responsibilities expertise, processes, and assessments, if HTA bodies were to Many of the HTA organizations tend to have different assess- set out to develop expertise on production processes.” ment procedures and criteria for judging the added value of a EFPIA and other representatives of research-based product. Furthermore, a growing number of HTAs are moving drug companies are also not keen about the idea of HTAs’ beyond the clinical domain to investigate aspects such as cost- scope being extended to R&D costs when dealing with cost effectiveness, budget impacts, ethical and legal issues, and effectiveness and impacts on healthcare budgets. “R&D costs broader social and economic questions. This shift is bringing are [not] relevant in setting reimbursement levels,” says the HTAs into what some drug producers would regard as bor- EFPIA spokesman. “Including R&D costs [in assessments] is not derline areas such as consideration of preclinical R&D costs, only difficult practically, as R&D costs are not attributable to process development, and choice of formulations. one single product or country, but are shared across multiple With some new medicines, acquiring a positive HTA can be projects and multiple regions. It is also inefficient. Setting as big a challenge as gaining authorization from a regulatory the reimbursement level in relation purely to the costs of agency. There can be gaps of several years between a drug development, including R&D, would mean rewarding inefficient being licensed in a country and being given the go-ahead research and production processes.” for reimbursement within its healthcare system. There are widening disparities in patients’ access to new medicines Cost effectiveness and access to medicines across the EU due to delays in reimbursement decisions. To Nonetheless, HTA organizations are participating in discus- speed up assessments by minimizing unexpected complications sions with drug companies about lowering their planned prices during investigation procedures, HTA bodies have been allowed for new medicines by cutting costs, including process costs, to join regulators in giving preliminary scientific advice early in to make the prices more acceptable. The United Kingdom’s the drug development process. The objective is that this HTA National Institute for Health and Care Excellence (NICE), one of guidance should concentrate on issues relating to the planning Europe’s largest and longest established assessment bodies and design of clinical trials so that they provide data relevant to responsible for HTAs in England, has been given the role by requirements of a technology assessment. the British government of vetting new oncology drugs, whose reimbursements costs are covered by a Cancer Drugs Fund The industry’s perspectives (CDF). Money available annually under the fund was recently Governments are under pressure, however, to encourage HTA increased by NHS England, part of the UK’s state-funded bodies to broaden their expertise so that they can have an National Health Service (NHS), more than five-fold since 2010 even greater influence on drug development beyond clinical to £340 million ($432 million) (1). trials particularly in areas such as cost effectiveness. But the To make the CDF drugs more quickly accessible to cancer pharmaceutical industry has made clear that this widening of patients after they are licensed, they are assessed by NICE responsibilities should not involve assessments of manufac- during their development on the basis of quality-adjusted

turing processes and their costs. life years (QALYs) or how many years a treatment adds to IMAGES RF/GETTY ZOONAR GLOBE:

12 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com a person’s life and the quality of those years. One QALY is Over the past few years, HTA agencies have been joining equivalent to one year of perfect health so that if a patient’s together through a European network (EUnetHTA) to carry state of health falls below that level, it is rated less than one out joint assessments so that they can share expertise more QALY per year. effectively, particularly in areas where there is a shortage of NICE has been setting a threshold of £20,000–30,000 per specialist knowledge within assessment bodies. “Collaboration QALY when deciding whether a new drug is cost-effective and and knowledge-sharing amongst HTA bodies can contribute should be approved for widespread use, according to a study to increased expertise and more efficient HTA systems,” by York University’s Centre for Health Economics (2). But it has Ancel.la Santos, policy advisor at Health Action International also been approving new technologies at more than £40,000 (HAI), a Dutch-based NGO campaigning on medicines access per QALY (2). issues, told Pharmaceutical Technology Europe. “Cooperation In October 2016, NICE jointly proposed with NHS England can be particularly relevant in the context of more complex a tiered system of categorizing new medicines by their cost- technologies and therapies,” she explained. “Collaboration effectiveness on the basis of QALYs (3). Medicines whose cost between HTA bodies should preserve high quality standards, effectiveness ratio fell below £10,000 per QALY could be put result in the improvement of methodologies and assessments through a “fast track” NICE assessment. Medicines based on where needed, and take into account local country highly specialized technologies, such as those for treatments specificities.” of rare diseases, would be given an upper limit of £100,000 per EUnetHTA launched in June, 2016 its third and biggest QALY to qualify for an HTA. Drug companies have been having joint action programme for the period 2016–2020 with the to lower their prices by cutting costs to bring their medicines objective of carrying out, with the help of mainly EU funds of within the QALY threshold. €20 million, 80 joint assessments or projects, compared to 20 NICE stresses that when calculating cost-effectiveness, it under the previous programme (6). In an impact assessment does not need to investigate production processes or overall of cooperation activities in HTAs, the European Commission, R&D costs. “Consideration of cost effectiveness does not warned that the latest joint programme may be the last to be require consideration of R&D costs,” an NICE official told financed by the EU (6). Pharmaceutical Technology Europe. “[Our assessments] are “The uptake of joint work at EU level (for use in) national based on patient outcomes measured in QALY with cost decision-making processes has remained low, leading to effectiveness measured in cost/QALY. The evaluation of duplication of work by national/regional HTA authorities,” said production processes is part of the role of the regulator and the commission’s study (6). “It is not rational to invest public NICE does not need to consider this.” funds into HTA co-operation at European level if the uptake of the work is not improved and the duplication of the efforts is Drug pricing, R&D, and production costs not avoided.” The big difficulty is that the EU states cling on to However, the political momentum behind calls for closer their right to reach their own drug pricing and reimbursement examination of the relationship between drug prices and R&D decisions. This independence is undermining the benefits costs as well as production costs has been gathering pace. of HTA co-operation and holding back the broadening of the The European Parliament’s environment, public health, and expertise in HTA bodies. food safety committee (ENVI) has demanded greater transpar- ency of research data and costs. “The cost of development References and clinical trials is crucial in order to set fair prices,” noted 1. NHS England, Appraisal and Funding of Cancer Drugs from Soledad Cabezon Ruiz, rapporteur of an ENVI report on EU July 2016 (including the new Cancer Drugs Fund) (London, options for improving access to medicines (4). “A fair price July 2016). should cover the cost of the drug development and production, 2. Centre for Health Economics, York University, Policy & plus a margin of profit,” she added. Research Briefing. Pharmaceutical Pricing: Early Access, The Amidst the potential for greater use of personalized Cancer Drugs Fund and the Role of NICE (York, March 2016). medicines resulting from the application of advanced 3. NICE and NHS England, Proposals for Changes to the technologies such as gene and cell therapies, production Arrangements for Evaluating and Funding Drugs and Other Health Technologies Appraised through NICE’s Technology is likely to take up a higher proportion of some individual Appraisal and Highly Specialized Technologies Programme drugs costs. As a result, these new technologies could (London, October 2016). raise the profile of manufacturing costs, in particular when 4. Committee on the Environment, Public Health and Food inconsistencies in production performance in the early stages Safety (ENVI), European Parliament, EU Options for Improv- of development can raise total R&D costs. ing Access to Medicines, Draft report 2016/2057 (INI) (Brus- sels, September 2016). Collaborations and joint assessments 5. Council of the European Union, Council Conclusions on The European Council, representing the EU member states Personalized Medicine for Patients (2015/C 421/03) (Brussels, governments, urged in 2015 the drawing up of central guid- December 2015). ance and criteria on HTAs of personalized medicines. It also 6. European Commission, Inception Impact Assessment, suggested that there should be more co-operation between “Strengthening of the EU cooperation in Health Technology HTA bodies in the assessment of the medicines (5). Assessment (HTA)” (Brussels, September 2016). PTE

Pharmaceutical Technology Europe JANUARY 2017 13 OUTSOURCING REVIEW

The Tide Stays High

Robust venture capital investment gives CDMOs and CROs a positive outlook for 2017.

year ago, the outlook for contract services was tide of early development by emerging bio/pharma A a little uncertain. Equity markets’ appetite for companies has risen thanks to the robust external public offerings from emerging bio/pharmaceutical funding environment. companies had significantly diminished: valuations The bio/pharma industry’s recent performance is of emerging bio/pharma companies, as measured encouraging, but what is really important is what the by the NASDAQ Biotechnology Index (NBI), had industry can expect going forward. There is a sense declined by 15% from their highs in mid-2015, that the outlook is positive but with some significant and by mid-February, they were off another 28%. uncertainties. Because contract development and manufacturing Jim Miller is president of organizations (CDMOs) and contract research US election impacts PharmSource Information organizations (CROs) get so much of their business Clearly, general economic sentiment since the Services, Inc., and publisher from externally-financed companies, the negative November 2016 presidential election has been positive, of Bio/Pharmaceutical energy surrounding emerging bio/pharma did not with an expectation that the regulatory environment Outsourcing Report, bode well for the industry. will be less restrictive and the United States Food and tel. +1.703.383.4903, The valuations and levels of public offering activity Drug Administration will be approving more drugs Twitter@JimPharmSource, in 2014 and 2015 were not sustainable, and the NBI more quickly. There have even been suggestions that a [email protected], has never gotten back close to the levels it reached venture capitalist might be appointed to run the agency www.pharmsource.com. in 2015. Nevertheless, fundraising by emerging (no appointments had been announced at the time this biopharma companies held its own in 2016. Financing column was written). However, emerging bio/pharma for emerging bio/pharma from venture capital, public investors haven’t been moved much by this news as equity, and partnering sources was ahead of 2013 the NBI has remained at the same level it has been at levels, and those companies showed no fear of for the past 12 months. spending liberally to progress their pipelines though Enthusiasm for the bio/pharma industry may have clinical development. Public reports for more than been dampened by the president-elect’s campaign 300 companies tracked by PharmSource show that promise to go after high drug prices, including R&D spending by those companies has risen every allowing Medicare to directly negotiate drug prices. quarter since the beginning of 2015. The dismantling of Obamacare could further reduce Not surprisingly, this has been great news for spending on drugs, especially in hospitals and other CDMOs and CROs. Most publicly-traded services institutional settings. Coupled with the aggressive providers achieved revenue growth well in excess efforts by pharmacy benefit managers to reduce of 10% in 2016 (based on interim results), especially private sector spending on drugs by reducing in those services that cater to clinical development utilization and prices, overall drug spending is likely (clinical supplies manufacturing, analytical services, to face considerable headwinds. That could dampen clinical packaging, and clinical research). Many new investment in the industry, especially if it CDMOs have told PharmSource that they are becomes more difficult for novel treatments to get operating near capacity, and customers may have to formulary access. wait as much as six months for a manufacturing slot. The significance of external funding can be seen Funding and investments by looking at early-phase clinical trials sponsored One positive indicator for CDMOs and CROs is the by emerging bio/pharma companies. Phase I and II robustness of venture capital investment. Venture clinical trial registrations by emerging bio/pharma capital money has always been more dependable companies, as recorded in clinicaltrials.gov, were up than public equity, even during the years of the global 55% higher in the first half of 2016 versus the first financial crisis. In 2016, even though public equity half of 2012 (see Figure 1) (1). Just over half of those dropped considerably, venture capital maintained companies (55%) are publicly-traded companies, a pace that was close to what it was in 2015 and

while 45% are funded by venture capital. Clearly the nearly 60% higher than it was in 2012. Looking ahead, Stockbyte/GettyImages image) (Spotlight

14 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com Outsourcing Review

according to the blog Life Sci VC, Figure 1: Ownership of emerging bio/pharma companies life-science venture funds are raising sponsoring clinical trials. record amounts of new money that can sustain emerging bio/pharma companies for an extended period (2). 60% Of course, few venture capital or public equity investors place bets 50% on emerging bio/pharma companies 40% with the expectation that they VC Owned will commercialize their pipeline 30% Public Company candidates on their own. Rather, they hope their companies will 20% be acquired, or at least have their 10% candidates licensed by, a global bio/pharma company. Acquired or % Trials by Sponsor Ownership 0% in-licensed products account for a Phase 1 Phase 2

third to a half of product approvals gained by global bio/pharma Source: clinicaltrials.gov; PharmSource analysis companies in recent years, and their reliance on externally-sourced candidates appears to be greater than for CDMOs and CROs. The biggest References ever. According to a report published risks will come from what happens 1. ClinicalTrials.gov. by Deloitte in December 2016, global to drug pricing and coverage; and 2. Life Sci VC, “Biotech Venture Capital bio/pharma companies are getting from a system-wide economic shock Mythbusting Redux,” 21 Nov. 2016, only a 1% return on their investment that negatively impacts the entire https://lifescivc.com/. in internal R&D (3). economy. The former is likely but over 3. Deloitte, Balancing the R&D So the stars seem to be aligning an extended number of years; and the Equation: Measuring the Return from

Figure courtesy of the author the courtesy of Figure for a continued healthy environment latter can’t be predicted. Pharmaceutical Innovation 2016. PTE

TASI TEST represents a new force in the packaging leak detection market by combining 3 industry leaders, Bonfiglioli Engineering, Sepha & ALPS. Our Pharma divisions, Sepha & Bonfig, have developed a range of innovative products designed to optimise packaging quality control processes in a pharmaceutical environment. These product lines include state-of-the-art equipment for: ' P#!#&"# ' "  "&"" ' ! $# %!& ' P $# " For more information contact  @sepha.com Visit usus atat Interpack Pharmapack 2017: Paris 2017: Hall  # 3 4 Booths L63 & &  #  C70

tasitest.com [email protected] +44 28 9048 4848 editor, [email protected]. Europe’s Pharmaceutical Technology Hallie Forcinio 16 Pharmaceutical Technology Europe Packaging Forum Forum Packaging is B blister packaging protect quality and enhance shelf life. shelf enhance and quality protect packaging blister Advances in materials and equipment for pharmaceutical Forward Moves Packaging Blister into the main unit. “We sell two feeder stations stations feeder two sell “We unit. main the into plugs that wheels on station afeeder and change changeover features includ quick Other tools. no requires and 10 minutes than expedite tooling changes, changeover takes less frequent changeovers (1). With hand screws to with lines and copackers to well-suited especially is preheating multi-zone and inspection inline with machinevolume runs, servo-driven the compact, lower for Designed 130 mm. of width index maximum and mm 90 of length index amaximum at minute 1 Figure MHI. of CEO and president Zaic, Gregory reports peelable),” and peel/push, (push, lidding CR for sealing design to had we so Japan, in requirement (CR) there. is no “There child-resistant packaging blister 400 nearly installed has and Japan pharmaceutical packaging largest second the as ranks Kogyo, Hatsujyo Maruho Parent company, support. technical Kyoto-based 24/7 and parts, spare maintenance, installation, US-based provides 2014, in MHI Established of parent company’s its best-selling . Hatsujyo Innovations (MHI), is an version American MHI Eagle blister packaging machine from Maruho . replace to wings the in wait options Pouch life. shelf maximizing and quality product innovations focus on protecting quality-control and Material equipment. downstream and upstream with integration and size, compact controls, servo flexibility, combine advances The MHI Eagle blister packaging machine (see the market, American North the in entry A new dosage forms, continues to evolve. Equipment Equipment evolve. to continues forms, dosage lister packaging, a common format for solid- ) operates at speeds up to 100 blisters per per blisters 100 to up speeds at ) operates JANUARY 2017 PharmTech.com

machinery company in machinery e recipe-driven format format e recipe-driven cartoner with dual stacking devices, integration of a of integration devices, stacking dual with cartoner aP3200 include variations potential Other . tuck accommodate could also but sealing carton hot-melt featured cartoner aP1600 with test. The one-lane CP400 blister packager integrated acceptance afactory to way its on line integrated an Nov. 2016) (6–9 showcased EXPO Pharma at Adisplay cartoning. for stacked are cards blister of pairs before blister other every on placed is insert an confirm Cameras parts. change minimizes and units stacking fault-prone intermediate eliminates transfer product Direct cartons. and inserts feeds punches and (perforates embosses), diecuts, and seals, doses, thermoforms, Mediseal Medipak’s is easily integrated with a printer or cartoner. and manufacturers other from feeders accepts downtime for cleaning. The Eagle blister packager minimizes and off-line cleaning feeder moves units Swapping Zaic. changeover,”says at swapped be can feeders so one-and-a-half of price the for We’ll be seeing more ... more seeing We’ll be A fully integrated, modular line from Körber Körber from line modular integrated, A fully t t t t t t t t  Advanced materials for materials improving Advanced  Pouches replacing cartons  leak testing Non-destructive  In-line inspection  Quick changeover features  Robotics systems Compact  equipment Integrated  or tailoring the package barrier. package the tailoring or

A-R-T/Shutterstock.com; Todd Arena/Getty Images Figures are courtesy of the author. 500 cartons per minute, the Integra Integra the minute, per cartons 500 to up and blisters 520 producing of Capable sections. cartoning and the for design balcony a features and space floor 10in m of Group. system fits The servo-driven blister packaging line from Marchesini Vintegrated 520 Integra the in role from the operator interface (5). controlled is flights cartoner the number of blisters transferred to The parts. change for need the eliminates and flights cartoner to transfers blisters from die punch A robotic pick-and-place module 100 blisters/80 per minute. cartons to up produces and system, control footprint, operates from a single acompact in results system unified fromcartoner Pharmaworks. The TC1 the and TF1e thermoformer the integrates line packaging x7.9 x2.8 3.5 to x 2.0in. (4). in. 0.6x0.5 approximately from range sizes Carton horizontally. cartons intermittent-motion loads cartoner integrated Estuchadora ACM 150 (3). Blipack’s feeders universal and semiautomatic, automatic, dedicated, and including printers accessories of range awide and cold-forming or is compatible with thermoforming and controller logic programmable electromechanical or driven by a be can system The maintenance. and changeover easy and quick with user-friendly operation and construction combines heavy-duty 240 blister packaging machine, The centerpiece, the Blistera 200- lines. cartoning and forming blister integrated also supplies Argentina, explains. Mediseal, at manager service Trepte, area Kai changes,” format for system by instructions detailed provides which HMI, the in is “All information the minutes. 30 than less to time changeover reduce helps and use of ease for interface (HMI) groups functions human/machineA sophisticated (2). minute per blisters 400 is line Maximum speed of the servo-driven and choice of roller or platen sealing. spiral conveyor, or dedicated feeder) (brush , roller dosing, automatic of lidstock, various dosing systems online for HAPA from printer Robotics alsoRobotics play an important Another turnkey blister in based acompany Blipack, 90 x150 (6). mm 90 x x16 35 90 x75 to from mm range sizes Carton available. is option measures 9 mm, although a 12-mm depth forming Maximum life. wear and tear and extends service system mechanicals protects from bath oil enclosed An changeover. cleaning andand straightforward quick ensures zones mechanical and electrical from loading product Separating system. insertion and andspeeds, a new leaflet pickup opening system to manage higher carton- adrum-type pusher, model and incorporates an innovative 320 Integra the succeeds Vline 520 foil blisters. 120 leak from Pfeiffe detector Figure 2: In AMI the standalone a Pharma demonstration, EXPO packaging cleaning machine and downtime. enables cuts off-line Figure 1: A removable feeder module on the MHI Eagle blister r Vacuum checked cold-formed retrofitted to shorten the forming forming the shorten to retrofitted (7). clearance line faster for surfaces smooth and changeover, format free tool- technology, drive and control latest the features model 300 BEC 2015, in the Upgraded minute. per cartons 700 blisters/300–500 outputting of capable 700, BEC lane three- the and minute; per cartons 500, rated at blisters/300–500 500 BEC dual-lane the minute; per cartons blisters/150–300 300 to up for model 300 BEC single-lane the models: three offers time, some for lines packaging blister integrated offered has which Existing BEC 300 systems can be be can systems 300 BEC Existing Systems, Packaging Uhlmann Pharmaceutical Technology Europe Packaging Trends JANUARY 2017 JANUARY 17 Packaging Trends

cycle, simplify cleaning, and minimize Time spans for the offline test or odour loss, nutraceuticals, abrasion marks on forming materials. range from 10–60 seconds. pharmaceuticals, unit-dose liquids, Uhlmann’s Rebuild Packaging Calibrated orifices quantify the and veterinary products (14). Systems Center performs electrical leak rate and provide an alert and mechanical retrofits using if seal quality is deteriorating. References genuine Uhlmann parts to extend Compatible with thermoformed 1. Maruho Hatsujyo Innovations, “At equipment lifespan and meet the or cold-formed blisters, testing Pharma Expo, Maruho Hatsujyo latest GMP requirements and legal a different blister only involves Innovations to Introduce Blister regulations. Upgraded equipment a simple fixture change. Machine Specifically for U.S. Market,” Press Release, 25 Aug. 2016. comes with detailed rebuild The VeriPac UBV leak detection 2. Mediseal, “Flexibility All Along documentation, validation services, system from PTI Packaging the Line,” Brochure, undated. and one-year warranty. Rebuilding Technologies and Inspection 3. Blipack, “Blister Packaging typically saves 30–70% compared combines vacuum with volumetric Machine 200-240,” www.bli- to the cost of a new machine (8). imaging to detect leaks in multi-cavity pack.com.ar/eng/factory/200. blister packs. The nondestructive htm, accessed 23 Nov. 2016. Carton alternatives test involves three steps: input the 4. Blipack, “Cartoning Machine ACM 150,” Cartons are the traditional secondary number of blister cavities; place www.blipack.com.ar/eng/factory/ package for blisters, but CR pouches the on the inspection acm150.htm, accessed 23 Nov. 2016. provide a lightweight, flexible plate; press start. In seconds, the 5. Pharmaworks, “TF1e/TC1 Line packaging option. To simplify display shows pass or fail, the (New!), the All-in-One Solution,” adoption of a CR pouch, the Child- volumetric measurement reading, www.pharmaworks.com/index. Guard CR track and slider from Presto and the location of any defective php?id=210, accessed 23 Nov. 2016. 6. Marchesini Group, “All4Pack Paris: Products has a Drug Master File cavity. The technology provides Marchesini Group Showcases the listing. In use, the caregiver moves rapid detection of defects as small Amazing Integra 520 V Line and the Child-Guard slider over a notch, as 10 microns in a test cycle that Two New Stand-Alone Machines,” pushes down on a tab and pulls lasts less than 15 seconds (12). Press Release, 22 Sept. 2016. back the slider to open the pouch 7. Uhlmann Packaging Systems, (9). CR pouches from Impak meet Innovative materials “Blister and Cartoner Module in ASTM (American Society for Testing Activ-Blister material from CSP One Productive Unit,” www.uhl- and Materials) D3475 CR standards. Technologies heat-stakes absorbent mann.de/products/blister-lines. Sliding tab or press-to-close CR material to the interior of blister html, accessed 23 Nov. 2016. designs require two-handed dexterity cavities. Silica gel and molecular 8. Uhlmann Packaging Systems, to open, making access difficult for sieve technology absorb tailored “Uhlmann USA to Ramp Up Machine Rebuilding Services at New Jersey toddlers but not for seniors (10). amounts of water vapour, oxygen, Facility,” Press Release, 24 Aug. 2015. or a combination of the two to 9. Presto Products, “Slide-Rite Child- control the internal atmosphere of Quality control Guard Track & Slider,” http://fresh-lock. Quality control systems confirm each cavity and protect product com/product-list/slide-rite-child-guard- blister packaging equipment is shelf life. The active feature can slider-zippers/, accessed 27 Nov. 2016. working properly. Systems, such be adopted without changing the 10. Impak, “Impak Offers the Largest as the camera-based IBIS inline footprint of the packaging line (13). Selection of Child Resistant blister inspection system from Another option for sensitive Pouches, Plus the Option for Pharmaworks, check product and products, Pentapharm LiquiGuard Labeling and Custom Print,” www. print on sealed blisters. Installed film from Klöckner Pentaplast, impakcorporation.com/flex- ible_packaging/child-resistant- inline or off-line, the vision system offers protection from package pouch, accessed 27 Nov. 2016. identifies flaws such as mis- leaching and moisture gain or loss. 11. Pharmaworks, “IBIS Inline Inspection,” shaped, damaged, missing, or The crystal-clear, autoclavable www.pharmaworks.com/index. rogue product, as well as incorrect laminate accommodates hot- php?id=271, accessed 23 Nov. 2016. color and foreign objects (11). fill liquids, gummies, and other 12. PTI Packaging Technologies and Seal integrity is checked on units emerging dosage forms. Features Inspection, “Introducing New such as the AMI 120 leak detector include a customizable moisture Non-Destructive Technology from Pfeiffer Vacuum (see Figure 2). barrier, excellent deep-draw for Blister The leak detector requires no tracer properties for complex blister at PACK EXPO International,” gas to nondestructively detect geometries, high heat stability (the Press Release, 2 Nov. 2016. holes as small as five microns, a transition temperature of the 13. CSP Technologies, “CSP Technologies, Inc. Introduces Activ-Blister sensitivity up to 1000 times better contact layer is 120 ºC), high slip Solutions for Customizable Product than the traditional destructive for quick release and increased Protection at INTERPHEX NYC,” blue dye dunk test. “Using helium productivity, and low leachability Press Release, 28 Apr. 2016. as a tracer gas boosts sensitivity and extractability, with excellent 14. Klöckner Pentaplast, “Pentapharm even more,” says Dennis Seibert, odour and flavour retention. LiquiGuard Films from Klöckner head of business development, Applications include chewables, Pentaplast,” Press Release, Leak Detection, at Pfeiffer Vacuum. formulations sensitive to flavour 26 Oct. 2016. PTE

18 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com We have come together to support all your outsourcing needs.

PCI Pharma Services, a market leader for integrated drug development and commercialisation

We have combined the expertise of Penn Pharma, Biotec Services International, AndersonBrecon and Packaging Coordinators to create PCI Pharma Services, an integrated pharmaceuticals provider positioned to support your drug needs from molecule to market. With drug development and manufacturing expertise, laboratory services, global clinical trial services, and commercial services for manufacturing and packaging, PCI supports over 50 product launches per year and medicines destined to over 100 countries around the world.

We invite you to learn more about how partnering with PCI can ensure the success of your next product launch.

Clinical Services Manufacturing | Packaging & Labeling | Global Storage & Distribution

Commercial Services Manufacturing | Packaging | Serialisation

© Copyright 2015 Packaging Coordinators, Inc. All Rights Reserved AndersonBrecon (UK) Limited trading as Packaging Coordinators, Inc. is a company registered in England and Wales with company number 02543975 and VAT registration number GB 549 7026 19 whose registered office is at Capital Law, Capital Building, Tyndall Street, Cardiff CF10 4AZ UK. VAT Reg. No. 762 3299 16 www.pciservices.com Penn Pharma, a PCI company, is a Trading Name of Penn Pharmaceutical Services Limited Registered in England & Wales No. 1331447 Registered Office: Capital Law, Capital Building, Tyndall Street, Cardiff CF10 4AZ UK. VAT Reg. No. 762 3299 16

Biotec Services International is part of Biotec Worldwide Supplies Group of companies, Registered in Wales NO 3483803. VAT Registration No. GB 108216149. 20 Packaging Trends Agnes ShanleyAgnes formulations and delivery systems, systems, andformulations delivery Pharmaceutical Technology Europe Primary packaging and container design reflects a move packaging design andPrimary to reflects container patient-friendly Patient-Centred Future Packaging’s Flexible, functionality and improve control,” improve and says. she functionality optimize to us allowed differences “These DeGrazio. says shape, and design adifferent for need the revealing up wound approach controlled This development. drug in practices (QbD) quality-by-design drive that principles same the using developed was plunger new The biopharmaceuticals. higher volumes of drug product—especially deliver to designed syringes, 2.25-mL in use for plunger a 1–3mL introduced West year, example, for this Earlier components. packaging West. at services technical and affairs scientific of vice-president DeGrazio, Fran says volumes,” dosing higher require may and viscous more are solutions the therefore, and, concentrated highly are produced being now are challenges. monoclonal “The anti appr patient-centred more to move the but systems, delivery new and autoinjectors with taken be now can clinic, or hospital the to visits requiring injection, repeated or (1). systems delivery and packaging novel for components develop to factors human and ergonomics in specialists with up teamed product development. for West Pharmaceutical example, Services, to approach their change to had have components system delivery and packaging of primary designers compliance, patient to improve develo pharmaceutical manufacturers Pharmasystems. Vanrx from technology filling automated fully and contained in Belgium. manufacturer, The contract Singota, recently bought Ingelheim’s Fremont, CA facility or Mithra Pharmaceuticals’ line components. these standardize to working are manufacturers and caps, and nested also but closures, and syringes nested only not of use the requiring operation, automated enclosed, fully to moving are operations fill/finish Some batches. and lots product smaller of manufacturing facilitate to designed being are risk of contamination, product B These changes in dosing have driven recent improvements in improvements recent in have driven dosing changes These infusion via taken be only could past, the in which, molecules, Large As picture. the of part only is manufacturing agile But Boehringer at found be may lines filling flexible of Examples manufacturers embrace more flexible processes that limit the the limit that processes flexible more embrace manufacturers packagingiopharmaceutical is JANUARY 2017 and more processes. agile manufacturing PharmTech.com

packaging and containment systems bodies and other biologics that that biologics other and bodies changing. As pharmaceutical oaches has presented technical p more convenient formulations formulations convenient p more says DeGrazio. extractables from entering product, minimize to designed was The Imlygic (talimogene laherparepvec). drug its contain to FluroTec stoppers, West’s on based system aclosure and vials CZ for opted had Amgen earlier, months Five container. primary SmartDose system delivery and the using but drug, the only not antibody, Repatha (evolocumab)— Amgen’s monoclonal approved Food and Drug Administration (FDA) minutes. several in drug of 3mL than more deliver can and patient the to adheres device delivery Smartdose West The oil-free. silicone FlurotecDaikyo plunger, the system is the with coupled When material. polymer, (CZ) a polyolefin Zenith cyclic Crystal Daikyo from made system acartridge uses which platform, come together in West’s SmartDose crucial for product integrity and and integrity product for crucial and preventing contamination is integrity system Maintaining testing Closure . syringe silicone-free 2014 a in for apatent received which W.L.Gore, including containers, glass on alternatives to silicone-treated working are companies of A number (2). syringes prefilled in aggregate to proteins some cause to found been has This contamination. particulate to led has which tungsten, or oil silicone contain not does it system, syringe a of part as used when addition, another benefit, says DeGrazio. In been has therapies, cell and gene some for required level nitrogen dry temperatures, even down to the transport and storage cold-chain lower withstand to ability CZ’s of substitutes glass Benefits In July 2016, the United States States United 2016, the July In designs component Improved

IMAGE COURTESY OF OMPI A-R-T/SHUTTERSTOCK.COM Packaging Trends

patient safety, says DeGrazio, and was inspired by the semiconductor Standardization efforts manufacturers accomplish this in industry’s Front Opening Unified Pod, The trend to nested systems began different ways, through improved a box of silicon disks that could easily with prefilled syringes, so they facility and workflow design, use be picked up and manipulated by a have been standardized to the of machine vision inspection and robot without operator intervention. highest level so far, says Deutschle. continuous monitoring on the plant These tubs of nested containers and Nested vials and cartridges are floor, and the use of higher quality closures allowed for a greater level just emerging on the market, he elastomers and barrier systems. of automation in fill-finish operations, says, and are being standardized. Improved integrity testing is also explains Greg Speakman, vice- Massignani adds that there is a crucial. president of sales and marketing for specific work group led by Ompi’s In August 2016, the United Vanrx, whose automated approach regulatory affairs manager that is States Pharmacopeial Convention to fill/finish was inspired by the entitled to redact the ISO Standard (USP) released updated its workcells of the electronics industry. for Ready-To-Use Vials and Ready- recommendations for container Becton-Dickinson came out with the To-Use Cartridges. closure integrity testing. The revised first nested systems nearly 30 years Vanrx’s system requires that United States Pharmacopeia Chapter ago, he says. containers and closures be placed <1207> outlines the analytical tests Ompi entered the market in in a nest to allow for robotic that should be performed to show 2007 with EZ-fill nested syringes, handling. Packaging component integral product safety, for instance, introducing vials and cartridges two vendors, including Daikyo Seiko, leak detection for vial and syringe years later, and nested closures for Datwyler, SCHOTT, SCHOTT KAISHA, systems, says DeGrazio. Before vials, developed together with Daikyo Ompi, ARaymond, and Vanrx the chapter was published, she Seiko, in 2015, says product manager established the Matrix Alliance in says, methylene blue dye testing Alessandro Massignani. 2016, to work on standardization was used in vacuum to find leaks. Nesting syringes, cartridges, vials and ensuring interoperability of Now, regulators realize that such and closures in standardized nest containers and closures. The key methods are more probabilistic than or packaging allows maximum goal is ensuring that a container determinant, she says, and subject flexibility from fill/finish equipment, from one vendor will work with to error. Among the methods that says Gregor Deutschle, business a closure system from another West uses and offers is helium leak development manager at SCHOTT vendor, without requiring extensive detection, which allows testing and AG, since fill/finish operations are retesting and integration by the validation down to -120 °C to -140 °C. performed with the containers end-user,” says Speakman. remaining in the nest. He points to Nested systems Schott’s adaptiQ vials, which allow all A small but growing part of the process steps to take place inside the components and packaging business nest, including checkweighing, freeze- is pre-sterilized and ready- to-use- drying as well as closure of the vials nested components. This approach with press fit caps, as an example. Contin. on page 31

Fluoropolymers for processing

Fluoropolymers are being used in systems that hold surfaces that prevent biopharmaceutical materials biopharmaceutical materials during processing and from interacting with container surface materials. storage. W.L. Gore’s covered Lyoguard lyophilization When preforming caps, at the clean bench, the trays feature a fluoropolymer membrane designed to company uses proprietary technology to minimize prevent product contamination and flyout. Storage static electricity buildup, which can attract particles. also poses challenges, since temperatures required Savillex has also improved overall factory flow and the for bulk drug product can be as low as -70 °C. Savillex inspection training it offers staff and customers for began to sell its containers to pharma in 2011, embedded particulates. The company also uses HEPA offering a line of perfluoroakloxy (PFA) and fluorinated filters extensively at the plant to prevent ethylene propylene (FEP) . These are single use, contamination, says Potter. but have a five-year shelf life, says Don Potter, PFA and FEP can be steam sterilized and director of marketing, and they can be especially pyrotreated but they cannot be irradiated. “We can useful for applications that require no trace metals or ship unsterilized to end users, or have the organics. containers sterilized by a third party,” says Potter. In Fluoropolymer bottles are traditionally extrusion the lab, the containers are widely used for analysis blow molded, but the company’s current owner with methods such as inductively coupled plasma developed a stretch blow machine that mass spectroscopy, or wherever trace metals are works with the materials, resulting in smoother analyzed.

Pharmaceutical Technology Europe JANUARY 2017 21 22 2017. Europe Pharmapack during solutions packaging unique of avariety display will manufacturers Pharmaceutical Pharmapack 2017at Display on Solutions Packaging New Packaging Trends Technology Europe Pharmaceutical of Editors The Pharmaceutical Technology Europe and medication reminders-to-use and end-of-product-life warnings (1). priming inhaler includes counter eDose The design. valve metering any eliminating the risk is of also miscounting. compatible with The technology spray, inhaler of detection direct offers technology sensing counter’s The 20-mm coated stopper. a offers also company The plunger. a1-mL and stopper coated 13-mm a include to line PremiumCoat the expanded recently Aptar elastomer. a barrier and to leachables that extractables be can released from the as acts which , surface film fluoropolymer athin with stoppers elastomeric of range 2017. anovel is Europe PremiumCoat Pharmapack at inhalers dose metered for Counter eDose the and stoppers elastomeric of range PremiumCoat company’s the display will Pharma Aptar stoppers Elastomeric P technology for their formulationtechnology (2). Charlottesville, VA, aids in customers selecting the appropriate packaging in located suite XCEL Services BlisterPro Pentaplast’s Klöckner quickly. more market to products bringing in customers assist to capabilities prototyping and packaging pharmaceutical offer XCEL Services BlisterPro company’s The -183 to lyophilized. and filling 120 ºC from ºC ranging moisture gain or loss. LiquiGuard provides protection from temperatures laminate film that sensitiv protects aclear, in thermostable packaged and formed be to semi-solids and XCEL at Pharmapack. LiquiGuard Services allows hot- and cold-fill liquids company’s line Pentapharm of pharmaceutical blister films and BlisterPro the to addition latest the LiquiGuard, introduce will Pentaplast Klöckner films blister Pharmaceutical Europe visit You can pharmapackeurope.com. Awards, honouring innovation in pharmaceutical packaging products. 2017 conference, Pharmapack Europe will also host the annual Pharmapack andcustomers, investors, partners, and forge new relationships. During the potential meet ideas, their showcase to companies start-up for floor show the on space 2017, adedicated Europe provides Pharmapack to addition anew Hub, Start-Up The services. and products innovative showcase to around the world. 70 countries than more from exhibitors 380 than more feature will which conference, the of anniversary 20th the marks year This products. Aptar’s eDose Counter is designed to enhance patient compliance. compliance. patient enhance to designed is Counter eDose Aptar’s To find out more about Pharmapack Europe 2017, Europe www. visit Pharmapack about more To out find companies for opportunities provides conference 2017The Pharmapack highlights a variety of pharmaceutical packaging and drug-delivery drug-delivery and packaging pharmaceutical of avariety highlights France, 2017 1–2 Feb. Paris, in from place taking Europe, harmapack during Pharmapack Europe 2017 at Hall 4 Booth M76. 2017 4Booth Hall at Europe Pharmapack during JANUARY 2017 PharmTech.com

e products frome products package leaching and

Pharmaceutical Technology Europe 2017 (3). Europe packaging solutions at Pharmapack desiccant its showcasing is Sanner lines. filling and dosing common all on requirements and can be processed regulatory all with comply solutions confusion with drugs. Both desiccant eliminates potential grid structure AdCap’s The protection. moisture offer capsules desiccant AdCap packaging. the inside capsules or tablets as such drugs sensitive ensure protection of moisture- and of made are desiccant AdPack capsules. desiccant AdCap and sachets, desiccant AdPack System, Guard Atmo the including solutions packaging desiccant multiple offers Sanner Desiccant packaging solutions . Gerresheimer, News Release, 9 Jan. 4. 2016, 19 Dec. Release, Press Sanner, 3. Klöckner Press Pentaplast, Release, 22 2. www. Releases, Press Pharma, Aptar 1. References (4). exposure oxygen and vapour water against molding process protection that offers injection an in product a multilayer Protect, Twist-Off Duma the showcase also will company The syringe. the of in preventing contamination assists material ceramic The ceramic. special a using created is syringe RTF Gx Luerlock the of cone the shape to used pin the tungsten, of Instead bore. the in cone syringe the shaping when metals occasionally remain behind is that traces of or tungsten other A common problem with syringes Lock Gx syringe at RTF Pharmapack. 1mL-long Luer metal-free company’s Gerresheimer will showcase the syringes Tungsten-free 2017, www.gerresheimer.com www.sanner-group.com. 2016,Dec. www.kpfilms.com. aptar.com/pharma

PTE

A-R-T & Nordroden/shutterstock.com High-Quality Gx® Glass Vials for Pharmaceuticals and Diagnostics

| High performance design 1 – 2 February 2017 | Paris, France | High barrier properties Paris expo Porte de Versaille | Superior resistance Booth G1 & H1

www.gerresheimer.com 24 Editorial Director Editorial Pharmaceutical Technology Europe uncertainty for the bio/pharma industry and and industry bio/pharma the for uncertainty of election Donaldunexpected Trump has created (1). process approval drug regulatory European the of apart remained UK the if benefit would companies drug and payers, however, experts, Regulatory argue that patients, EU. and UK the for applications marketing separate file to companies require may and EU regulations from UK the sever could Brexit” A“hard change. may UK in the medicines for pathway approval regulatory future the developed, are market UK the investment in drug development projects (1). for research; academic andfor to access capital funding Court; Patent Unified the and Initiative Medicines Innovative the in UK the by participation continued countries; between ingredients active and of drugs movement of medicines; new approval and licensing the EUon and UK the between agreements establishing include challenges Other (EMA). Agency relocation of the London-based European Medicines potential the including issues, industry fundamental faces pharma industries, all for issues top are UK the in working EUnationals of status the and companies pathway.approval aregulatory and funding, development and research drugs, affordable including issues, social and political, business, of arange for forward away together piecing of task the with companies bio/pharma and leaders, business policymakers, left has and surprise On the other side of the Atlantic Ocean, the the Ocean, Atlantic the of side other the On for drugs how defined have EUregulations While EU and UK between relationships business the While from the European Union took the world by by world the took Union European the from he United Kingdom’s ‘Brexit’ vote to separate JANUARY 2017 PharmTech.com

2016 to 22 from 25 in 2015. Similar-biologic product product 2015. 25 in Similar-biologic 2016 from 22 to in slipped drugs generic for of approvals number the to 16 declined 20 from in approved 2015;drugs and orphan of 41 number 2015. with in The compared recommended for marketing authorization in 2016 were drugs new, non-orphan 29 only total, this Of 2015. 97in with 2016, in compared authorization marketing for 81 drugs recommended (CHMP) for forHuman Products Medicinal Use Committee US in (3). the a of approvals drop EMA’s total, In in were down 2016approvals in EU, the mirroring Drug agenda. its on challenges regulatory and development, financial, productivity, crucial other has industry bio/pharma the changes, Brexit the Beyond examination of such agreements. such of examination closer for campaigned which Trump administration, the under scrutiny additional to subject be may and (2). India and China as such areas, needed in resources concentrating and avoiding lowering costs, duplicating inspections, facilities making for multiple products markets, thus for inspections other’s each on rely EUwould the frominspectors FDA and other regulatory groups in and investigators initiative, the 2016.in Under Trade progress and Investment Partnership—made of negotiations for theEurope—part Transatlantic in authorities (FDA) regulatory and Administration Drug and Food US the between inspections GMP for cooperation. A proposed mutual reliance agreement presents potential roadblocks to regional regulatory The initiative, however, is part of a trade agreement agreement atrade of part however, is initiative, The

Sashkin/shutterstock.com 2017 European Bio/Pharma Outlook

approvals did increase, from two in similar to the 5.9% growth during the States, Germany, United Kingdom, 2015 to seven in 2016 (4–5). past five years. Future growth will be Italy, France, and Spain. While drug approvals were down, generated by autoimmune, oncology, The US remains the top spender the global demand for medicines and diabetes treatments. on drugs (US$461.7 billion), followed continued to increase. The by China (US$116.7 billion), Japan QuintilesIMS Institute, in its annual (US$90.1 billion), Germany (US$43.1 projections for global drug sales billion), France (US$32.1 billion), Italy (6), estimates that global medicine (US$28.8 billion), UK (US$27 billion), spending will reach nearly US$1.5 Brazil (US$26.9 billion), Spain (US$20.7 trillion on an invoice price basis by billion), and Canada (US$19.3 billion), 2021; the total volume of medicines QuintilesIMS reports. consumed globally will increase 3%. The types of therapies and use of innovator versus generic drugs, The report predicts that specialty Price controls will contribute to however, will vary depending on drugs to treat chronic, rare, or genetic limit drug sales growth in Europe where patients live. diseases will be more widely used, to 1–4% to 2021, the report states. Consumption of newer drugs in particularly in the US and European Estimated growth rates are 4–7% developed markets, more generic markets, thanks to the approval in the UK, 1–4% in Italy and Spain, drug use in pharmerging markets, of breakthrough medicines and a 2–5% in Germany, and -1–2% in plus patent expiries, discounts, greater focus by payers on drug France. The impact of Brexit on the and rebates will result in a 4–7% value and performance. Spending on UK pharma market is expected to compound annual growth rate such therapies, which was 20% of be “modest at worst with a 1.5% (CAGR) to 2021, slower than the all medicines spending 10 years ago, slower growth rate in the downside nearly 9% CAGR in 2014 and 2015 will rise to 30% in 2016 and to 35% scenario” (6). Weak economic when expensive new hepatitis drugs by 2021 and will represent half of the growth, unexpectedly high drug distorted the annual growth rates, but medicine purchases in the United costs for innovator drugs in 2014

Uncertainty across the pond

The election of populist candidate Donald Trump as Regulatory outlook president of the United States shocked many and Another campaign theme—reducing the number of created unease in the public and private sectors, but it federal regulations perceived as roadblocks to also boosted the financial outlook for bio/pharma business—may impact FDA and its efforts to expedite companies, at least in the short term. The investment the approval of innovator and generic drugs. The community initially viewed a Trump administration as number of warning letters issued by FDA for more pharma-friendly compared to a potential Clinton adulterated APIs or drug products nearly doubled administration. Bio/pharma stocks rallied after from 2015 to 2016 (3), with many letters addressing Election Day; however, ongoing concern about drug data integrity issues and citations at overseas pricing, payer pressure, and economic questions still operations. The agency also worked to clear the created uncertainty (1). backlog of generic-drug applications, but has been During the presidential campaign, candidate Trump hindered by ongoing staff shortages. and the Republican Party promised to repeal and The 21st Century Cures Act, signed into law by replace the Affordable Care Act (ACA) of 2010, which President Barack Obama in December 2016, includes extended healthcare to millions of Americans. Bio/ support for research on regenerative medicine and pharma companies benefited from the increased pool development of antibiotics and treatments for rare of patients requiring medicines, but also paid higher conditions. Other provisions are designed to fees and made concessions on drug prices. streamline the drug approval process using novel US drug industry performance clinical trials designs and study modeling and permit Drug approvals did not live up to expectations in 2016. drug companies to use real-world evidence to support Only 22 new drugs received US Food and Drug approval of added indications for marketed medicines. Administration (FDA) approval, compared to 41 in 2014 References and 45 in 2015. Fewer submissions and more complete 1. A. Brown, EP Vantage 2017 Preview, Report, Evaluate response letters contributed the lower number of Pharma (December 2016). approvals, FDA noted. The number of applications 2. C.A. Challener, Pharmaceutical Technology 41 (1) 26-29 received by FDA through 9 Dec., 2016, however, (January 2017). surpassed the average number of new molecular entity 3. FDA, Inspections, Compliance, Enforcement, and Criminal Investigations, www.fda.gov/ICECI/ filings for the past decade (2) suggesting a steady EnforcementActions/WarningLetters, accessed pipeline of new applications for 2017. Dec. 20, 2016.

Pharmaceutical Technology Europe JANUARY 2017 25 2017 European Bio/Pharma Outlook

and 2015, and a desire to control a barrier to creating value in an R&D and Beyond,” FDA Blog, 7 Dec., 2016 costs will encourage Europe-based organization. http://blogs.fda.gov/fdavoice/index. policymakers to be more cautious Companies have demonstrated php/2016/12/the-mutual-reliance-initi- in adopting new medicines in the greater efficiency in drug ative-a-new-path-for-pharmaceutical- future. development through “nimble inspections-in-europe-and-beyond/ accessed 20 Dec., 2016. decision-making, empowering 3. C.A. Challener, Pharmaceutical key decision-makers, accepting Technology 41 (1) 26-29 (January 2017). Amid the clamor about controlling greater risk, making quick kills, and 4. European Medicines Agency, Monthly drug prices, drug company embedding a rigorous but dynamic Statistics Report: November 2016, executives are examining R&D process for funding projects,” the www.ema.europa.eu/docs/en_GB/ methods and declining returns. The study authors reported (7). document_library/Report/2016/12/ cost to bring a drug to market, as One anticipated source of WC500218559.pdf accessed estimated by the Deloitte Centre gaining efficiencies—extensive 10 Jan., 2017. for Health Solutions (7), declined outsourcing—has not delivered on 5. European Medicines Agency, Meeting slightly from US$1.576 billion in expectations, the study authors Highlights from the Committee for 2015 to US$1.539 billion in 2016, report. Sub-optimal partner Medicinal Products for Human Use perhaps due to shorter cycle times management by drug companies (CHMP) 12-15 December 2016, Press for breakthrough designations. The and operating models that hinder Release, (16 Dec., 2016). study also concluded that companies externalization contribute to 6. M. Aitken, M. Kleinrock, and D. with less volatility in the therapy-area less-than-expected results from Nass, Outlook for Global Medicines focus of their late-stage development outsourcing arrangements (7). through 2021, Balancing Cost and programmes outperform those that Value, Report, QuintilesIMS Institute, continually change the focus of their (Parsippany, NJ, December 2016). drug-development efforts. Company 1. Evaluate Pharma, Brexit: Laying Out 7. K. Taylor, M. Stockbridge, and S. Shah. size is also a factor. The study of a Path for UK Healthcare, Report, Balancing the R&D Equation, Measuring 12 leading biopharma companies (London, 2016). the Return from Pharmaceutical revealed a negative correlation 2. D. Corrigan, “The Mutual Reliance Innovation 2016, Report, Deloitte between company size and predicted Initiative: A New Path for Centre for Health Solutions returns, and indicated that scale is Pharmaceutical Inspections in Europe (London, 2016).

Perspectives from bio/pharma personnel

In the 2016 Pharmaceutical Technology/ Optimistic outlook Pharmaceutical Technology Europe annual Respondents based in Europe were more optimistic employment survey (1)—which was conducted after about the 2017 prospects for their company; more the Brexit vote, but prior to US presidential elections— than 60% the respondents predicted that their respondents from around the globe shared similar company’s business will improve this year, up from perspectives about employment-related prospects, 50.4% last year. In contrast, only 54.8% of the but also expressed varying opinions about business respondents from North America said business at prospects for bio/pharma. their companies would improve and 16.6% predicted More respondents from Europe worked at generic- business would decline. drug bio/pharmaceutical companies (28% in Europe The EU-based audience also was more positive in vs. 14.5% in North American) than innovator their outlook for the bio/pharma industry in general companies (19.5% in Europe vs. 31.1% in North for 2017: 46.4% said business would improve in 2017, America). The respondents from Europe also worked up from 39.5% in 2016. while the numbers were up for for smaller companies, were slightly younger, and two consecutive years, the numubers are still down held more advanced degrees. from the 55.3% who expected improvement for 2015. Business activity was up slightly 2016; 42.3% of the Predictions for business growth in the bio/pharma EU-based respondents reported an increase in industry as a whole over the next five years were business at their company over the previous year, more optimistic than for individual companies. similar to 2015 when 40% of EU-based respondents Nearly two-thirds (62.9%) of the EU-based said business at their company increased (2). respondents predicted that business will improve; More than one-quarter of the respondents (26.7%) however, 14.4% expect business to improve reported that their company had been through a overseas, but not domestically. merger or acquisition in the past two years, nearly the References same percentage as in 2015 and up from the 19.7% 1. 2016 Pharmaceutical Technology/Pharmaceutical reporting in the 2014 survey. A similar number of Technology Europe Annual Employment Survey. respondents reported a company downsizing or 2. 2015 Pharmaceutical Technology/Pharmaceutical restructuring (24.8% in 2016 vs. 28.2% in 2015). Technology Europe Annual Employment Survey.

26 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com Pharma&Biotech

Focused on Your Success

Committed to Global Innovation for Human Health

Lonza has been a reliable partner in the life sciences industry Why Outsource with Lonza? for over 30 years. Our experience in biological and chemical – Full range of services from preclinical risk assessment to development and manufacturing has allowed us to create a full-scale commercial manufacturing broad platform of technologies and services for fine chemicals, – Advanced technologies and optimized processes to advanced intermediates, active pharma ceutical ingredients streamline your product pipeline (APIs), functional ingredients, biologics, cell and viral therapies. – 10 contract development and manufacturing sites worldwide – Experience with worldwide regulatory authorities We are committed to continued innovation with a focus on future – Track record in meeting accelerated timelines associated scale-up technologies and emerging markets. Whether you are with breakthrough therapy designated products an established pharmaceutical company or an emerging biotech, – Dedicated project teams committed to comprehensive and Lonza is prepared to meet your outsourcing needs at any scale. timely communications – Lean, sustainable processes that minimize waste and environmental risk For more information, contact us at: North America: +1 201 316 9200 Europe and Rest of World: +41 61 316 81 11 [email protected] www.lonza.com/oursites Services, Intertek. ofdirector Biological 28 Ashleigh Wake Pharmaceutical Technology Europe is characterization and quantitation of oligonucleotide therapeutics. and quantitation characterization Characterization and and Characterization of Oligonucleotide Oligonucleotide of T product registration in respect to identity, purity, quality, and and quality, purity, identity, to respect in registration product support to required data the of overview an provide documents (4). These control quality to respect in thinking current detailing control ofquality oligonucleotides. documentation withofficial surrounding to respect expectations issued have Agency Medicines European the or (FDA) Administration Drug and Food US the neither yet, as subsequently, and guidance, providing of terms in perspective aregulatory from challenges many to led has molecule small or alarge either as definition ready of lack (3). This moiety abiological of typical more interactions involves level acellular on which action, of mode in adiversity however, display to traditional small-molecule Oligonucleotides, pharmaceuticals. directly them likens that amanner in synthesis chemical solid-phase (3).synthetic contaminants any as well as interest of oligonucleotide the of quantitation and a specifically fundamental to aspect, facilitate characterization developments, has advancement also in technology been analytical these support to (2). Undoubtedly clinic the in success increasing more sophisticated delivery systems, and most importantly, of of the oligonucleotides, basic understanding biology better a chemistries, improved including of factors to a combination stages of development. programmes clinical 140 active than more detailing ClinicalTrials.gov with strong, be to appears therapies these for pipeline development The States. United the in use for expectations. initial these meet to failing growth of level actual the with limited been has stories success of number however, the (1). recently, years Until 30 than more for Despite the lack of formal guidance, FDA has issued papers issued FDA has guidance, formal of lack the Despite Oligonucleotides are generally produced through a synthetic attributed be can development oligonucleotide in resurgence This approved have been drugs 2016, antisense of September three As Impurity Analysis Analysis Impurity therapeutics hastherapeutics been apparent in the pharmaceutical industry he potential and anticipation surrounding oligonucleotides as JANUARY 2017 Analytical technologies play a key role in the the in akey role play technologies Analytical Therapeutics PharmTech.com

for oligonucleotides in various for analysis. criteria fundamental are of an oligonucleotide sequence nucleotide the of and confirmation weight molecular the of Determination material. test the of identity the verify to that orthogonal approaches be used control it analytics, is recommended quality the of many with as molecule, the of nature complex the Given testing Identity programme. characterization typical I Table programme.complex analytical and adiverse represent involved analytics actual The strength. sequence of oligonucleotides. When determination of both mass and the for alternative aviable provided tandem methods (MSMS), have particular, in and spectrometry mass mass and sequence. and thus make clear on assignments spectra good obtain to ability the oligonucleotides (5), hinder which can of weights molecular large and low thermal stability, complexity, nature, polar the by hindered be often can alternatively, approaches, species.length Mass spectrometric chain short of analysis the to ways, some in restricted, is success of andtime-consuming the likelihood relatively and complex often are digestion involving Methods used. havemass spectrometry been widely followed by Gilbert) Maxam modified Sanger) or chemical methods (e.g., such methods (e.g., as enzymatic Historically, digestion approaches information. this gain to applied be can methods Several expectation. aregulatory thus and molecule confirmation of the of identity the of terms in analysis for criteria oligonucleotide are fundamental the nucleotide sequence of an weight and confirmation of Determination of the molecular andsequence structure Oligonucleotide Advancements in high-resolution provides an overview of a an overview provides

Egorov Artem/shutterstock.com Formulation: Oligonucleotides

Table I: Characterization of oligonucleotide drug substance. Criteria Analysis Methodology

Mass spectrometry Molecular weight Size exclusion chromatography (SEC) Optical rotation (to clarify that stereochemistry Description and is controlled) physiochemical pH characteristics Moisture content

pKa

Hygroscopicity

Assay High-performance liquid chromatography (HPLC) Inductive coupled plasma (ICP) Assay/impurities Counter ion Atomic absorption (AA)

Duplex content SEC Enzymatic method (e.g., Sanger) Sequencing Chemical method (e.g., modified Maxam Gilbert) Enzymatic digestion followed by mass spectrometry (MS) Enzyme digestion and HPLC of nucleosides. For enzyme-resistant Nucleobase composition oligonucleotides, transformation may be required; however, in these cases, the process should be shown not to affect other parts of the molecule. Nuclear magnetic resonance (NMR) Melting temperature (T ) m Circular dichroism (CD) Capillary gel electrophoresis (CGE) Chain length Polyacrylamide gel electrophoresis (PAGE ) analysis 31P NMR for assessment of phosphodiester, phosphorothioate, Structure Internucleoside Linkage methlyphosphonate, and any other modified phosphate Molecular backbone composition 31P-NMR plus strong anion exchange (SAX)–HPLC phosphorothioate to phosphatediester (PS/PO) ratio HPLC Chromatographic profile SAX (for phosphorothiates) Lambda max and min for acidic, basic, and aqueous solutions. UV spectra Determination of extinction coefficient Spectroscopic profile Fourier transform infrared spectroscopy (FTIR), 1H-NMR, other NMR including stereochemistry considering intact mass, normal Such high resolution readily monophosphate (AMP) and resolution instrumentation can allows discrimination of nucleosides Deoxyguanosine monophosphate only be used to obtain the average differing by only 1 mass unit, such (dGMP), both of empirical formula molecular weight; high-resolution as Cytidine monophosphate (CMP) C10H14N5O7P and a monoisotopic mass mass spectrometry has, however, (monoisotopic mass 323.05185 Da) of 347.06308 Da). In discrimination facilitated the determination of and Uridine monophosphate (UMP) between species of this type, accurate mass. This method is based (monoisotopic mass 324.03587 Da), structural differences are relied upon on obtaining negative ion spectra including distinguishing between the for definitive identification. In the of the oligonucleotide followed by 13C isotope of CMP and 12C isotope of AMP and dGMP, for example, deconvolution. The accuracy of these of UMP, which effectively have the the position of the oxygen atom measurements is typically less than equivalent mass at a lower resolution differs, which can be distinguished 5 ppm, and as such, the mass can (324 Da). by MS analysis and thus allow these be used as an aid to establishing the Quinn et al. (7) also detailed how isobars to be distinguished. empirical formula of the molecule, tandem MS can be used to confirm The benefit of these advanced which is in turn used to postulate or the presence of truly isobaric MS-based methods is further confirm structure (6). nucleosides, such as Adenosine demonstrated when considering

Pharmaceutical Technology Europe JANUARY 2017 29 Formulation: Oligonucleotides

identification of the position of increasing bioavailability. An example presence of denaturants, and modified nucleosides, a feature that of the effect of this engineering is hybridization conditions. Altering

could not be established from the that introduction of phosphorthioate the Tm by manipulating external or earlier digestion/chromatography linkages increases resistance to environmental factors is often used approaches. nucleases, but the incorporation to increase solubility of a product of too many bonds can reduce the or to enhance in-vivo stability of the Chain length function of the species. material. Despite improvements in the Modifications are, however, a Many algorithms exist for

automation and understanding necessity, and as such, powerful determination of theoretical Tm. of the chemistries involved in techniques that allow continued These theoretical values aid product oligonucleotide synthesis, and monitoring of the distributions development. For determination of

despite the most ardent post are required. SAX–HPLC and actual Tm, however, NMR and circular synthesis clean-up, it is inevitable nuclear magnetic resonance (NMR) dichroism (CD) provide the best 31 that there will be some heterogeneity spectroscopy, in particular P NMR, methods for establishing the Tm of an with regards to chain distribution provide powerful data in this respect oligonucleotide. in the final material. Monitoring of to monitoring linkage. SAX–HPLC is this distribution presents a further particularly useful where quantitation Impurities determination fundamental aspect of quality is required (i.e., discrimination of In addition to confirmation of core control. the amounts of phosphate diester structural and physiochemical features, continued monitoring of the purity and levels of product- In addition to confirmation of core structural and and process-related impurities physiochemical features, continued monitoring presents a fundamental attribute for of the purity and levels of product- and process- oligonucleotides in continued quality related impurities presents a fundamental attribute control. for oligonucleotides in continued quality control. Product-related impurities include the following: t Addition sequences (n+1, n+2, etc.) The most accepted methodologies or phosphorothioate diester). t Deletion sequences (n n-1, n+2, for performing this assessment 31P NMR can yield powerful data etc.) are capillary gel electrophoresis about the type of internucleoside t Phosphodiester analogs (CGE) and anion exchange–high- linkers (phosphodiester P=O, t Depurinated sequences performance liquid chromatography phosphorothioate P=S, methyl t Partially deprotected sequences (SAX–HPLC), given both methods’ phosphonate, phosphonate, or any t Aggregated sequences. inherent ability to separate other modified phosphate), the When considering impurities truncated species. Each approach nucleobase, and oligo backbone involving addition or deletion of offers advantages over the other. composition. NMR also provides sequence, the methods of choice are CGE methods require little or no information on the ratios of various SAX–HPLC or CGE, when considering development to reach maximum species such as that between chain length. For the other performance and can generally be the P=O and P=S; however, this potential product-related species, a applied to larger oligonucleotides technique is restricted to ratio and combination of chromatographic and without loss of resolution over that other techniques needed to give true spectroscopic methods are applied to can be prevalent with the HPLC amounts. cover all relevant components. approach. Alternatively, SAX– Aside from product-related

HPLC methods are generally more Melting temperature (Tm) impurities, residual species reproducible, the columns last longer, Melting temperature is often originating from the process require and the response of and amount of considered the most critical quality monitoring, and if necessary, loading into the instrument are not attribute of an oligonucleotide. This specifications set. Such species affected by species of differing mass property relates to the temperature include: to charge ratios (8). at which a double-stranded oligo t Organic volatile impurities denatures and separates into (OVI) or residual solvents, Internucleoside linkages two single strands. The melt typically quantified by gas

Introducing modification to a temperature, or Tm, is defined as the chromatography (GC) with flame nucleoside linkage has been a critical temperature at which 50% of the ionization detection (FID) or mass feature in the advancement of molecule is double stranded and spectrometry (MS) oligonucleotide therapeutics. Such 50% single stranded, also known t Inorganic molecules metals, alterations help to overcome the two as the molecule being classed as inorganic salts, catalysts, cleavage

main challenges affecting the efficacy 50% annealed. Critically, Tm can reagents, and counterions typically of these molecules, specifically, be influenced by external factors, quantified by inductively coupled delivery to the target in vivo and such as salt concentration, the plasma (ICP), MS, or OES.

30 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com Formulation: Oligonucleotides

Conclusion com/2016/06/oligonucleotides-opportuni- In support of continued quality control ties-pipeline-challenges/, accessed 12 Dec. of oligonucleotide therapeutics, a 2016. vast array of analytics is required to 4. Rao V.B. Kambhampati, Points to Consider for comprehensively control structural, the Submission of Chemistry, Manufacturing, physiochemical composition, as well and Controls (CMC) Information in as the purity and impurities of the test Oligonucleotide-Based Therapeutic Drug material. Looking forward, some of the Application, presentation at DIA Industry challenges facing the resurgence in and Health Authority Conference on: these therapies and the growing pipeline Oligonucleotide-based Therapeutics of oligonucleotides can be effectively (Bethesda, MD, April 2007). addressed through application of these 5. M. Smith, Rapid Commun Mass Spectrom. 25 sophisticated analytical approaches and (4) 511-25 (2011). continued advancements in analytical 6. R. Houghton, “Oligonucleotides: The Next technology. Big Challenge for Analytical Science,” Chromatography Today, March 2011. References 7. R. Quinn et al., Mass Spectrom. 48 (6) 703– 1. A. Aartsma-Rus, Molecular Therapy 24 (2) 712 (2013). 193–194 (2016). 8. Analysis of Synthetic Deoxyoligonucleotides 2. R.L. Juliano, Nuclei Acids Research, published by Anion Exchange HPLC and Capillary Gel online 15 Apr. 2016, doi: 10.1093/nar/gkw236 Electrophoresis, Waters Cooperation, poster 3. B2B Labs, Oligonucleotides: Opportunities, at the 16th Annual Symposium of Column Pipeline and Challenges, http://b2blabs. Liquid Chromatography (June 1992). PTE

Packaging’s Flexible, Patient-Centred Future — contin. from page 21

Alliance members recently shared test can take a long time in a bulk filling plant, results involving vials and press-fit caps because all containers must be handled with their shared biopharma customers, individually and thus require a large and plan to release findings publicly during number of spare parts. In addition, he the first quarter of 2017. But the move notes, classic bulk lines can be very large to nested vials and caps reflects trends and require a lot of expensive clean room that are not going away any time soon: a space. shift from blockbusters to smaller niches Using nested components in a flexible of high-value drugs; more frequent/fast line reduces the need to invest in washing, product changeovers in multi-product water for injection, and utilities, and also facilities, and a move from large facilities reduces maintenance and validation in developed markets to smaller facilities costs, says Massignani. “The containers in more remote parts of the world, says travel in packaging that prevents glass- Speakman. to-glass contact, reducing rejection rate. Another important shift is that This approach adds value, not only by component packaging suppliers are improving product quality but because it taking over services once handled by shifts responsibility for the sterility and pharma companies, says Deutschle. “In cleanliness of primary packaging from the using ready-to-use nested components, pharma manufacturer to the packaging our customers want to eliminate the components supplier,” he says. need for preparation of the containers prior to filling. Therefore, we take care of References depyrogenation, washing, and packaging 1. C. Evans, “The Critical Role of Human as well as sterilization.” Factors and Usability in Improving medi- Flexible filling represents a major cation Adherence,” IPIMediaWorld.com, change from standard fill/finish 22 June 2016, http://ipimediaworld.com/ equipment, which is geared toward high- incorporating-patient-perspective-critical-role- speed, large production volumes, and human-factors-usability-improving-medication- often dedicated to a single container type adherence/, accessed 12 Jan. 2017. or drug, Deutschle explains. Changeover 2. A. Siew, BioPharm International, 29 (11), 38 from one container format to the next (2016). PTE

Pharmaceutical Technology Europe JANUARY 2017 31 PEER-REVIEWED

A Statistical Decision System for Out-of-Trend Evaluation

Niels Væver Hartvig and Liselotte Kamper

valuation of data from stability studies is a central part Eof the control strategy of pharmaceutical products and is a GMP requirement (1). The purpose is to ensure the safety and efficacy of the product by confirming that the stability is as expected and that it will continue to meet quality specifications until expiry. Stability studies can be part of the development programme for new products or the ongoing stability programme for marketed products. The studies are typically conducted both at long-term storage conditions and at accelerated conditions. For stability studies on marketed products, the objective is to confirm that the stability profile follows the trend of earlier batches. Unexpected results may either indicate that the batch is out of trend or that the result is out of The authors present a set of statistical decision trend (OOT). A typical approach to evaluate the data is to rules based on linear regression models that can be consider the following three questions (2): implemented in an automated trend system to assist t Is the latest result within the expected range, or is the stability studies. The models combine historical result substantially different from what is expected? The stability and analytical method data with data latter is known as an analytical alert and would usually from stability studies, and allow the responsible be related to the analytical procedure or the handling of person to routinely evaluate stability results based the stability sample, and more rarely to the actual sta- on statistical tools, without the need for expert bility of the product. statistical assistance. The system provides a t Does the stability of the batch follow the expected trend fast and standardized framework for evaluating compared to historical stability data? Or are there indica- parameters that approximately follow a linear tions that the batch degrades in a different manner than degradation path or are constant. observed earlier, which could indicate a special cause event has occurred in the production of the batch? This is known as a process control alert and will often lead to the conclusion that the batch is OOT. t Will the product comply with specifications throughout the shelf life? In the event of a process control alert, *Niels Væver Hartvig, PhD, is a principal specialist, the batch is known to deviate from the historical [email protected], tel.: +45 30790913, and expectations. The stability should be examined and Liselotte Kamper is a chemist, both at Novo Nordisk A/S, evaluated to ensure that the batch stays within the Smørmosevej 17-19, DK-2880 Bagsværd, Denmark. specifications. When this stability is questionable, a

Submitted: 22 Feb. 2016. Accepted: 7 Apr. 2016. compliance alert is raised. The evaluation can be performed subjectively by an analyst, but it requires long experience with the analytical CITATION: When referring to this article, please cite it as N.V. method and the product and its distinct properties. Also, Hartvig and L. Kamper, “A Statistical Decision System different analysts or different laboratories may conduct for Out-of-Trend Evaluation,” Pharmaceutical Technology 41 (1) the trending; they may have different experience and 34–43 (2017).

evaluate the data differently as a result. However, an CORONADO/SHUTTERSTOCK.COM

32 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com WWW.CAPSUGEL.COM ENGINEERING MEDICINES TO LIFE

RISING TO THE CHALLENGE Tomorrow’s complex medicines face challenges to overcome low bioavailability and optimize drug delivery. This calls for a partner with the credibility, ingenuity and flexibility to deliver both the product and process design required to make your compound a commercial reality. With a unique range of technology and integrated product development from design to commercial manufacturing, Capsugel is that partner.

© 2016 CAPSUGEL BELGIUM NV ALL RIGHTS RESERVED. Peer-Reviewed

Figure 1: Illustration of the trend system. LIMS is well by zero or first-order kinetic reactions, which lend laboratory information management system. JMP is the themselves to linear regression analyses. Parameters that computer programme by SAS Institute. do not develop linearly must be evaluated, for instance, by tolerance interval methods by time point (3), or by more advanced kinetic models of the stability profile. These Ongoing stability Parameter table data with historical data methods will not be considered here. (LIMS) (JMP) An overview of the system is provided in the following sections. Statistical details are deferred to the appendix.

Automatic pre- System setup processing of data The system is illustrated in Figure 1. The system supports with statistical results (JMP) a work flow where the stability responsible person rou- tinely evaluates and releases results in a stability study as they are available. Stability data are stored in a laboratory Evaluation of alerts by information management system (LIMS). To evaluate the stability responsible trend questions discussed in the previous section, his- person torical data and data on the analytical variability of the method are needed. These data are stored in a database with tables for each product. objective evaluation requires data from different sources The combination of the two data sources and the to be combined, namely the precision of the analytical statistical analysis and presentation of results is method and the stability trend of historical batches and implemented in a computer programme (JMP, SAS Institute) their associated uncertainty, and this is a burden both (6), but other systems for data analysis and visualization practically and statistically. can be used. The evaluation of results and alerts is Statistical tools can control the risks of false alarms, conducted on a computer screen. when the product and result are actually within the expected range, and the risk of overlooking an OOT. The The parameter table with historical data factors of uncertainty that need to be considered are: Historical stability data are summarized in a parameter t How much historical data are available—how well is the table (see Table I) for each product. The table should be expected slope determined? based on batches and results that are representative of t Are there historical batch-to-batch variations in the slope? the current product and analytical methods. t What is the intermediate precision of the analytical The parameter table should be established based on method and how well is this determined? statistical analysis of historical stability data that are t Is the variation in the current stability study comparable representative of the current product. For new products, to historical intermediate precision, and if so, what is typically data from the new drug application (NDA) stability the combined estimated precision? studies and other development stability studies will t How much data are available in the current study? be used. For marketed products, the body of historical t How much confidence is there in the predicted value of routine stability data can be used. the batch when extrapolating to end-of-shelf life? The analysis of the historical data should be based on a Unless a system is in place that facilitates the regression analysis, in which the average stability trend combination and statistical evaluation of data in an is determined. In the model, each batch should have its automated and standardized manner, the evaluation of own intercept to account for batch-to-batch variation in stability data will be laborious and may require expert the starting level. If the stability slope varies slightly from statistical assistance, which is usually not readily available batch-to-batch due to random variations, for instance in at all the facilities where data are generated and evaluated. raw materials or input factors, a mixed model with random A number of different approaches for evaluating slopes can be used (5). stability data from a statistical perspective have been The intermediate precision of the analytical method proposed in recent years (2–5). In this paper, the authors should preferably be estimated as the residual variation in consider only parameters that follow a linear stability historical stability data, because this estimate will cover trend (or are constant). In this approach, the analysis long-term variation in the method and also any other is based on linear regression models that combine the variation in stability studies, for instance, due to sampling efficiency of a parametric statistical model with the and handling of the samples. Alternatively, method practical aspect of being relatively simple and intuitive. validation data or variation in control samples can be used. From the authors’ experience, the vast majority of The construction of the parameter table is typically a

parameters that are followed in stability are approximated large task and may require a cross-functional team AUTHORS. THE OF COURTESY ARE FIGURES

34 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com Peer-Reviewed

Table I: Information on specifications and historical data contained in the parameter table. The information is provided for each parameter and storage condition. LSL Lower specification limit

USL Upper specification limit

Shelf life Expected shelf life (months) Expected stability slope in absolute units per month. This value is the estimated average slope from Expected slope historical stability data from representative batches. Standard deviation of the expected slope (in units per month). This value represents the uncertainty of Std. err. slope the estimated slope and optionally also historical batch-to-batch variation in the slope. Intermediate precision of the analytical methods in absolute units. This can be estimated as the Intermediate precision residual variation in historical stability data, or alternatively, the analytical method validation study can be used. Degrees of freedom of the intermediate precision estimate. This depends on the number of results D.f. used to determine the intermediate precision.

of analytical chemists, product responsible chemists, Figure 2: Example of the graphical illustration of an and statisticians. It is advisable to ensure careful analytical alert. The latest result is marked with a documentation and control of the parameter table because red triangle, because it, with high confidence (99%), does not follow the trend of the five previous results it is the cornerstone of the stability trend evaluation. (marked with a dashed grey line). The vertical bar Generally, the parameter table need only be established at the latest result indicates ±3 times the standard once for each product, but it may be necessary to update deviation of the analytical method. the table over time if there are changes to the stability profile of the product or to the analytical methods, or if 110 the initial parameter table is based on a relatively small body of stability data and more precise estimates are obtained over time. 105 The parameter table summarizes all the historical knowledge of the product and the analytical methods 100 in a single table. Thus, there is a wealth of information in the table, and the creation of the table ensures that

Component A (%) 95 the expectation of the stability study is clear across the organization. By using the same parameter table for trending, consistency in the evaluation of the data across 90 persons, departments, and sites is ensured, which is an 0 3 6 9 12 15 18 21 24 27 30 Time Point (Months) important benefit of the system. Linear Fit Latest time point excl. Routine trend evaluation Expected Slope When conducting routine trending, stability data are retrieved from the LIMS and combined with the param- eter table. The system processes the data and presents a graph for each parameter, batch, and storage condition. corresponds approximately to ±3 standard deviations The graphs illustrate the data and summarize the statistical around the expected value. evaluation of the three trend questions. The historical stability slope in the parameter table is not used in this evaluation, but the historical intermediate Is the latest result comparable with the results precision of the method is used to calculate the variance previously seen for the same batch in the study? of the result. This trend is evaluated by a prediction interval based on The result of the analysis is indicated graphically by the stability results for each batch, excluding the latest plotting the data with the regression line, calculated with result. If the latest result falls within the prediction the latest result excluded, and by overlaying ±3 standard interval, it can be concluded that it follows the trend seen deviation error bars on the latest result. This approach so far, within the expected uncertainty range. provides a simple visual check for whether the result is Typically, a 99% prediction interval will be used to have within the expected range. The conclusion of the statistical a reasonably low risk (1%) of a false alarm. This interval analysis is illustrated visually by plotting the latest

Pharmaceutical Technology Europe JANUARY 2017 35 Peer-Reviewed

Figure 3: Example of a graphical illustration of a in (7) by evaluating if the 95% confidence interval for the process control alert. The results of the batch are batch intersects the specification limit before the end of indicated with open red triangles to indicate that shelf life. A one- or two-sided confidence interval is used the slope of the batch is statistically significantly depending on whether the specification is one- or two- lower than the slope of historical batches at a 1% sided, respectively. significance level (indicated with the dotted grey line). If the batch is confirmed to be OOT and there is less than The statistical significance evaluation includes both the 95% confidence that it will comply with the specification uncertainty of the slope of the current batch and the during shelf life, a compliance alert is raised (see Figure 4). standard deviation of the historical slope estimate. The evaluation of criticality is not only a statistical exercise, 110 but the statistical result may be used to evaluate the effect of reducing shelf life or other mitigations.

105 Practical use of the system In the practical use of the system, all data for a given time 100 point are evaluated and a graphical overview of the dif- ferent parameters, batches, and storage conditions pre- sented. The graphical illustrations of alerts make it easy to

Component A (%) 95 get an overview of the data. In case one or more alerts are identified, summary tables with estimates and statistical details are available to interpret the findings. 90 0 3 6 9 12 15 18 21 24 27 30 When evaluating alerts, the trend responsible person Time Point (Months) should be aware of a number of pitfalls and understand

Linear Fit the limitations of the methods used: Latest time point excl. t Rounded and truncated results: The trend analysis Expected Slope requires data with sufficient resolution. In particular, impurity data are often rounded to one decimal and truncated when they are below the limit of quantifica- result with a red symbol, if the result is outside the 99% tion. It is important that a database with the unrounded prediction interval. An example is provided in Figure 2. results is available for the trend analysis; if not, the trend system may not analyze impurity data correctly. Is the development of the parameter comparable to the t Non-linear trend: The system assumes a linear trend development of the same parameter in historical studies? over time (or no trend). This approach is typically rea- This trend is addressed by a regression analysis, in which sonable, but complex biological reactions or physical the estimated slope of the current batch is compared with parameters are not necessarily linear. In this case, the the expected slope from the parameter table. Based on a results of the system should be interpreted with much t-test, the statistical significance of any difference can be care, and trending may need to be conducted by other assessed, accounting for the uncertainty of both the cur- methods, for instance, the by-time-point method (2). rent estimated slope and the expected slope. The uncer- t Multiplicity: A number of statistical tests are con- tainty of the expected slope can express both estimation ducted for each time point. For instance, if three uncertainty and, if relevant, random batch-to-batch varia- batches are followed at three different storage condi- tion in the slope (5). Typically, a significance level of 1% will tions and five parameters are evaluated for each, a total be used to avoid too many false alarms, corresponding to of 45 tests are conducted. With a significance level of the 99% intervals used above. 1% for each test, there is a risk of 1-0.9945=36% of at The result of the analysis is indicated graphically by least one false alert. Because there is no correction for plotting the regression line for the batch (the green line in this risk, it is important that the stability responsible Figure 3) as well as a line with the expected slope (dotted person is aware of the risk of a false alert and uses good line in Figure 3). If a statistically significant difference is judgement when evaluating alerts. observed, all points can be plotted with a separate Colour t Independent results: It is an assumption in the analysis to provide the stability responsible person with a clear that all results are independent. When this is not the visual indication that this statistically significant difference case, for instance, if two determinations are obtained needs to be evaluated and possibly investigated further. in the same analytical run, there is a risk of over-inter- preting findings and getting too many false alarms. The Can compliance with the specification limits be correlation between multiple results can be handled sta- expected to be maintained until the end of study? tistically using random effects models, but this method This analysis is conducted following the principles is difficult to automate in a system like this.

36 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com Peer-Reviewed

t Only the latest result is evaluated: Previous OOT Figure 4: Example of a graphical illustration of a results in the same study should be excluded before compliance alert. The trend line and 95% confidence the analysis; otherwise, these previous OOT results may region is colored red to indicate a process control alert, mask new OOT results. The system supports a work because the slope of the batch is significantly different flow where the OOT evaluation is conducted routinely from historical batches, and a compliance alert is after each result, and, therefore, only the latest result is issued because the confidence interval intersects the evaluated. specification limit of 95% before end-of-shelf life (here t Patterns across batches: The system analyzes each 30 months). The confidence region for the slope is batch, parameter, and storage condition separately, based on the data from the actual batch only. giving a relatively simple framework, but it means that patterns across similar batches or storage conditions 110 are not discovered. These patterns must be evaluated subjectively or by more advanced statistical analyses in 105 specific cases. t Number of results available. The system can, in principle, estimate the stability slope based on two results, using the 100 historical standard deviation as an estimate of the residual variation in the data. But clearly, the analysis will have low Component A (%) 95 sensitivity until more time points are available. The computer system should be validated for GMP-use. However, by building the system on existing validated 90 computer systems, the validation effort is relatively 0 3 6 9 12 15 18 21 24 27 30 Time Point (Months) smaller than if the system was built from scratch. Linear Fit Comparison with other methods Latest time point excl. Expected Slope As discussed, the methods presented rely on linear trend models with normally distributed errors. They are, there- fore, less general than OOT methods that do not rely on these assumptions, such as the ”change-from-previous” with the current batch and the fact that a pooled vari- type methods and by-time-point methods presented in ance is used in the test. If the standard error of the his- references 2 and 3, but they provide a simpler and more torical slope includes random variation between batches, efficient setup when the assumptions are fulfilled. the framework is similar to the random coefficient The methods can be compared with other published regression (6), where the model is used to set limits for regression methods as follows: individual results. t Analytical alert: The method presented here is very sim- t Compliance alert: The method presented is the same as ilar to the regression control chart method (3–5) based used in reference 7, where batches are not pooled and on a prediction interval. A difference, however, is that the each batch is thus considered individually. authors’ method uses a pooled variance based on the historical variance and the variance in the present study. Conclusion and further development This approach will increase the power of detecting an OOT, The trend analysis system provides the trend responsible provided that the variation in the historical data is compa- person with exact and reproducible results for evaluating rable to that of the current study. If the historical variance stability data. It makes the evaluation of data objective is not entered in the parameter table, the authors’ test and standardized, and provides greater flexibility in terms simplifies to the regression control chart method. of who does the trending. t Process control alert: The method presented compares The system provides valuable summary measures for the slope of the current batch with the average slope of each batch, such as the estimated slope with confidence historical batches by a t-test, allowing for uncertainty in limits, a statistical test for whether the batch is the estimated slopes and random batch-to-batch varia- comparable with historical batches, and the expected tion in the historical slopes. As such, the interpretation of shelf life based on extrapolation of confidence intervals. the test is similar to the slope-control chart method (3), The system makes it easy to account for the different though the statistical framework is slightly different. sources of uncertainty in the evaluation of the data and If the standard error of the historical slope accounts for thus provides control over the risk of false alarms and the uncertainty in the slope only, the method is similar to the risk of overlooking an OOT. test for poolability of batches (7), except for the fact that The system is relatively simple to implement, validate, all the historical batches are pooled before comparison and maintain, and can be based on a statistical software

Pharmaceutical Technology Europe JANUARY 2017 37 Peer-Reviewed

package such as JMP and existing database solutions, is first assumed that only a single result is obtained per such as LIMS. The statistical methods strike a reasonable time-point, and that xn is the latest time point. compromise between being relatively simple, based on The underlying statistical model is a linear regression linear regression model for each batch, yet sufficiently model, complex to handle, for instance, mixed effect models with Y = α + β x + ε , ε ~ N(0, σ 2), i = 1,...,n random variation in the slope between batches. i i i i Generating the database of parameter tables for all products requires analyses of historical data. Though this effort is a prerequisite for conducting a trend analysis, with all observations independent. Let x and Y denote whether a trend system is used or not, the practical the averages, work of establishing, documenting, and maintaining the 1 n 1 n parameter tables in a system such as this should not be Y = ∑∑Y,,x = x n i n i underestimated. i=1 i=1 The system is not designed to encompass all parameters, and some level of “manual” trending should, therefore, and let SPDYx and SSDx be given by be expected even with this system. Parameters that do n not follow a linear pattern or ordinal responses cannot be SPDYx = ∑Yi (xí − x), analyzed by the system currently. Also, impurity data that i=1 are truncated below limit of quantification may need to be n 2 trended by other methods. One could extend the system, SSDx = ∑(xi − x) . for instance, by including functionality for transforming i=1 responses to linearize the trend, or to include tolerance intervals methods. Still, it is important that the results of the The maximum likelihood estimates of the parameters _ analyses are intuitive and easy to interpret, and this feature and ` are then given by should be a cardinal point when extending the system. SPD ⎛ ⎞ ˆ Yx ⎜ 2 1 ⎟ Acknowledgement β = ~ N ⎜β,σ ⎟ SSDx ⎝ SSDx ⎠ The system has been developed by a team of stability , responsible persons in Novo Nordisk. In particular, the ⎛ x2 ⎞ ˆ ⎜ 2 1 ⎟ authors acknowledge valuable discussions and input αˆ = Y − βx ~ N⎜α,σ ( + )⎟ ⎝ n SSDx ⎠ from Marika Ejby Reinau, Jens Krogh Rasmussen, Helle , Lindgaard Madsen, Lone Steenholt, Carsten Berth, and and the residual variance m2 is estimated by

Karin Bilde. n 2 1 ˆ 2 2 2 s = ∑(Yi −αˆ − βxi ) ~ σ χ (n− 2) /(n− 2) n− 2 References i=1 . 1. EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Chapter 6. Evaluation of shelf life _ 2. PhRMA CMC Statistics Stability Expert Teams, Pharm. Technol., 29 (10), The (1- )-confidence limit for the regression line at time point x is given by 66 (2005). 3. PhRMA CMC Statistics and Stability Expert Teams, Pharm. Technol. 27 x − x 2 (4), 38–52 (2003). α + βˆx ± t s 1 + ( ) ˆ 1−α / 2,n−2 4. A. Torbovska and S. Trajkovic-Jolevska, Pharm. Technol., 37 (6), 48 n SSD x , (2013) 5. ECA, Laboratory Data Management Guidance; Out of Expectation (OOE) where tp,f is the upper p-quantile of the t-distribution with and Out of Trend (OOT) Results (draft, 15 Aug. 2015). f degrees of freedom, and s is the square-root of the esti- 6. JMP Statistical Software, SAS Institute Inc. mated residual variance s2. 7. ICH, Q1E, Evaluation for Stability Data (Step 4 version, 2003). The estimated shelf-life is established by looping over values of x and determining the largest x where both the Appendix: Statistical details upper and the lower 95% confidence limits are within the The following section contains the statistical details. specification limits. Consider data from a single parameter, a single If the specification is two-sided a two-sided 95% _ batch at a single storage condition. Let Y1,...,Yn be the confidence interval is considered by setting = 0.05. If results available for analysis and let x1,...,xn denote the the specification is one-sided, a one-sided 95% confidence corresponding storage time in months. For simplicity, it interval is calculated by setting _= 0.1.

38 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com Peer-Reviewed

Pooling of variances Under H0, this will approximately be t-distributed For the OOT-tests a pooled variance is used, with f degrees of freedom, where f is calculated by Satterthwaite’s approximation n− s 2 + f s 2 2 ( 2) ip ip ⎛ 2 ⎞ s 2 = s pool pool f ⎜ + s 2 ⎟ pool , ⎜ SSD 0 ⎟ f = ⎝ x ⎠ 2 ⎛ 2 ⎞ 4 s pool s f = n− 2+ f ⎜ ⎟ / f + 0 pool ip. ⎜ SSD ⎟ pool f ⎝ x ⎠ 0 . 2 Here s ip is the intermediate precision variance and fip is the degrees of freedom, both provided in the parameter Notice that when one or both of the degrees of freedom table. are infinite, some of the terms in the denominator will be 0. If both degrees of freedom are infinite, f will also be infi- For early time points, n-2 will be small, and the nite, and t follows a normal distribution. intermediate precision variance provided in the parameter The p-value is calculated as table has to be used to conduct tests for OOT. In this case, 2 2 s pool will primarily be given by s ip. On the other hand,

for late results, the residual variance contains valuable p = 2()1− F (| t | ( information on the precision of the analytical method t( f ) , in practice. As n becomes larger, the residual variance will weigh increasingly more in the pooled variance. A where F is the cumulative distribution function of a t-distri- prerequisite for pooling the variances is that the provided bution with f degrees of freedom. intermediate precision represents the current variation in the method. OOT test for latest result The OOT test for the latest result is conducted by first fit- x Y When fip is set to missing in the parameter table, it is ting the above model, but with the latest time point ( n , n ) 2 2 2 _ ˆ s 2 interpreted as f = ∞ and therefore s = s . If s is excluded. Let ˆ n , ` n , pool,(n) etc. denote the estimates thus ip pool ip ip ( ) ( ) missing in the parameter table, only the residual variance obtained. If the latest result deviates significantly from the 2 2 _ˆ + `ˆ x is used, i.e. s pool = s . predicted value based on the previous data, (n) (n) n , it is an indication that the result is out-of-trend; either because OOT test for slope of a laboratory error, an error in the handling of the sample, The test for whether the batch is OOT is based on the or for other reasons. `ˆ 2 0 Y ~ N(+ ,m ) expected slope and the standard error of this, s0, both It is initially assumed that n n and the test for + = _ + `x provided in the parameter table. It is assumed that the OOT is then a t-test for the hypothesis H0: n n . The `ˆ N ` m 2 expected slope follows a normal distribution, 0 ~ ( 0 , 0 ) , t-statistic is given by where the normal distribution expresses the uncertainty of the expected slope and/or an expected batch-to-batch variation in the slope. Y −αˆ − βˆ x t = n (n) (n) n In the parameter table, the degrees of freedom f0 for ⎛ x − x 2 ⎞ the standard error s could be entered if relevant. It was 1 ( n n ) 0 s 2 ⎜1+ + ( ) ⎟ found that in practice, this parameter was often difficult pool,(n) ⎜ n− SSD ⎟ ⎝ 1 x,(n) ⎠ to obtain, and the degrees of freedom are, therefore, by default set to missing, which is interpreted as f0 = ∞.

f The OOT test for the slope is a t-test for the hypothesis: which follows a t-distribution with pool ,(n) -degrees of ` = ` H0: 0 . The t-test is given by freedom.

βˆ − βˆ Multiple results at each time point t = 0 When multiple results are given for one or more time s 2 points, it is assumed that all observations are independent. pool + s 2 SSD 0 The analysis is conducted as described above, and an OOT x test for the time point is conducted for each individual result. PTE

Pharmaceutical Technology Europe JANUARY 2017 39 Testing Solutions; and senior engineer Integrity 40 test. decay pressure point-of-use sensitive ahighly of The describe authors the development and validation Bag Assemblies Leak Testing of Single-Use for Point-of-Use Validating aMethod Jean Marc Cappia Hogreve Marc Carole Langlois Management Technologies; manager,product Fluid Biotech. Stedim Sartorius at all Management Technologies, Fluid Management Product & Marketing VP group is Pharmaceutical Technology Europe is is senior senior is

S decay test method used for the point-of-use leak test at the user site site user the at test leak point-of-use the for used method test decay apressure of validation the describes article This Biotech). Stedim 2D, Sartorius (Flexboy 2Dstorage for decay pressure of means during storage, shipping, and bags single-use the to occurred damage no ensures (3). This steps process critical in used bags single-use all on test leak point-of-use enhance patient and operator safety and product high-value losing of risk the reduce can biomanufacturers Technical for Phar Requirements of Harmonization for Council International with accordance the bag chamber. and welds, the film, the of integrity the ensure policies control Quality control. process ensuring and validation, process performing principles, lifecycle. quality-by-design do this They by applying product entire the across integrity container-closure of assurance provide bag. per $1 to million $100,000 between be could failures bag of cost The astatement. in said Amgen at Development Process scientist, PhD, principcal Ding, Weibing materials,” and time of loss subsequently, and, products drug or fluids process of assemblies (1, 2). “A lack of robustness can lead to contamination of integrity the maintaining and transparency, material raw control, change supplier reliability, chain supply assurance, quality include challenges these that show surveys Industry address. to industry the for challenges new raised naturally has storage, product drug and substance drug as such applications, critical more into technologies such of Today, expansion the quality. product on impact agreater have when integrating single-use assemblies into processing steps that confident increasingly becoming are and technologies single-use from derive can they benefits the maximize to want biopharmaceuticals of Manufacturers times. cycle shorten flexibility, and improve In this article, a leak test method was validated to detect leaks by by leaks detect to validated was method test a leak article, this In in and strategy management risk quality their of part As bags single-use of suppliers established costs, To these avoid manufacturing by providing opportunities to reduce costs, costs, reduce to opportunities providing by manufacturing ingle-use technologies have tr JANUARY 2017 PharmTech.com

handling at the user site. maceuticals for Human Use Q9, ansformed biopharmaceuticalansformed by performing a non-destructive aby non-destructive performing and without Restraining Plates Restraining without and FlexibleNonporous Packages with Test Leak for Decay Pressure for Test Leak F2095-01: Standard ASTM from derived was method test The system ( the of sterility the and integrity the maintain that conditions under test the of performance the permit to line filter vent asterile of installation the requires This testing. leak pre-use and applications process critical of to meet the specific requirements adapted been have pre-use for bags 2D LFlexboy 50 to mL 50 of designs test. the during frombag stress mechanical the protect holders the Furthermore, required. reliability and sensitivity test the achieving for critical is This pressure. test ahigher at and volume bag inflating reproducible and small a with test leak the of performance allow holders The reduced. is and environmental heat transfer is eliminated effect masking potential Any test. the during holder steel stainless the with contact direct in not is bag the of surface film the spacers. By using porous spacers, porous with plates metal two of consisting each holders, bag two with tester. The bag tester was equipped system with 4 Sartocheck Plus Bag BT FlexAct the using performed were validation and development and instrument. hardware test Bag Integrity andmethods Materials detection limit. leak the and decay, pressure parameters, the maximum allowable the validate to out carried then was study validation Acomplete time. pressure, stabilization time, and test toperformed pre-determine the test first was study parameter preliminary 4Sartocheck plus Bag tester. A the and BT FlexAct the Lwith 50 to mL 50 from bags Flexboy of the industry toaddress. industry the new challengesraised for hasnaturally applications critical into more technologies of Expansion Pressure decay test method. L. 50 to mL 50 from 2D bags Figure 1 Figure ). Test method (4). (4). The The

NicoElNino/shutterstock.com EXHIBITION & CONFERENCE 1 & 2 FEBRUARY 2017 PARIS EXPO, PORTE DE VERSAILLES, HALL 4

Pharma’s dedicated packaging & drug delivery event

INNOVATION NETWORKING EDUCATION

NEW: Pharmapack Start-up Hub International Meetings Conference Pharmapack Awards Programme Learning Lab Innovation Gallery Exhibitor & Visitor Cocktail Party Symposium Innovation Tours Networking Areas Workshops

Follow the link: FREE TO ATTEND bit.ly/2cE4k3N REGISTER NOW!

NEWS, WHITEPAPERS & EVENT PROGRAMME ON

#PharmapackEU WWW.PHARMAPACKEUROPE.COM Single-Use Manufacturing

to pre-determine the stabilization Figure 1: Flexboy 2D standard bag design for pre-use leak test. time and test time parameters necessary to detect a defect reliably over the volume range of the bag configurations. The range contains Scope of the validation bags with 10 different volumes from for the leak detection 50 mL to 50 L. For each of the 10 bag sizes, three non-defective test Filter Test Line samples, and three defective test samples were prepared. Defects were introduced into film samples with a laser drill and flow calibrated hole. All 60 samples were tested at a fixed 300-mbar test pressure. For each test run, four different stabilization times of 60 seconds, 120 seconds, 180 seconds, and 240

IN seconds were used. The pressure drops were continuously measured and reported every second across the entire test time from 0 to 240 seconds during the four different stabilization time test runs. Final Final connection connection The minimum, the mean, the maximum, and the standard deviations (σ) of the measured pressure drops were calculated for Figure 2: Pressure decay test. the four different stabilization times separately, with non-defective and defective test samples for each Test pressure Pressure different bag volume. The optimum stabilization time and test time were stabilization decay test chosen to provide a selective test 300 method capable of differentiating defective bags from non-defective Pressure decay limit bags (i.e., the points where the error bars [± 3 σ] from the defect 200 is distinguished from the error bars [± 3 σ] from the non-defective Non-defective bag measurements). Initial results showed Defective bag that, for tests performed with a 100 120-second stabilization time and

Pressure (mbar) 90-second test time, a difference between the observed pressure drops of defective and non-defective 0 test samples could be detected 010with a probability of 99.9%. A safety Time margin was then applied by doubling (min) the stabilization and test times to avoid false positive and false negative results during normal operations. Once the test pressure has been film, welds, and ports of the bags. These timings were selected for the set and allowed to stabilize, the Because the validated test method subsequent validation study. system measures the pressure is non-destructive, it is compatible Test method validation. The decay and compares the result to with performing pre-use leak tests purpose of the validation study an acceptance criteria determined on 100% of bags used at a biologics was to verify the ability of the pre- during the development and production facility. established test method and test validation of the method (Figure 2). parameters to detect a defect The pressure decay test method Results reproducibly and accurately over developed detects defects according Test method development. The aim the volume range of the bags. The

to the leak-rate specification on the of the initial phase of the study was validation study was performed with Figures are courtesy of the authors.

42 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com Single-Use Manufacturing

Figure 3: Pressure drop intervals of ± 3 σ around the mean values for defective and non-defective test samples at 240 seconds stabilization and 180 seconds test time. Parameter study | 240s stabilization time /180s test time

100 Defective bags 90

80 +3 Mean value 70 -3

60

50

40 Pressure drop [mbar] 30 Non defective bags 20

10 No overlapping between defective and non defective bags with a 6 confidence interval 0 50 20 10 5 3 1 0.5 0.25 0.15 0.05 Bag volume [L]

Defective Non-defective

a statistically significant number of bags from different routine Table I: Final test parameters from the validation study. production lots to provide a robust Test pressure [mbar] 300 validation and test method. For each of the 10-bag volumes, 32 Stabilization time [seconds] 240 non-defective test samples from Test time [seconds] 180 production with representative raw material and process variability, Maximum pressure drop [mbar] 3.1 and 32 test samples with a defect were used. This represented a total of 640 samples tested during the full range of bags from 50 mL to knowledge, the first point-of-use the validation study. Every defect 50 L to avoid false positive or false leak test capable of detecting film sample was checked for its negative results under real testing down to 10 μm defects in 2D bags, calibrated hole size before it was conditions (Figure 3). The final test irrespective of their volume. The used. Tests were performed using parameters established during these sensitivity of the test is independent the pre-determined test pressure of studies are provided in Table I. of 2D bag size. 300 mbar, stabilization time of 240 seconds, test time of 180 seconds, Conclusion References and a defect size. The authors developed and 1. Aspen Brook Consulting LLC, 6th This study allowed the validation successfully validated a pressure- Annual Survey of the Single Use of the pre-established test decay leak test for 2D bags using Bioprocessing Market 2014 (Aspen parameters and the setting of commercially available equipment Brook Consulting LLC, 2014). a maximum allowable pressure and proved that it is a robust 2. Bioplan Associates, 12th Annual Report and Survey of decay specification at 3.1 mbar. The and predictive method for the Biopharmaceutical Manufacturing validated pressure decay method reliable detection of leaks. Using Capacity and Production (Bioplan was capable of reliably detecting the method, non-defective bags Associates, 2015). defective bags from non-defective gave results below the maximum 3. ICH, Q9 Quality Risk Management (ICH, bags with a given leak detection limit pressure drop specification. The 2005). in less than 10 minutes including bags into which a defect was 4. ASTM F2095-01: Standard Leak Test installation and testing. deliberately introduced gave results for Pressure Decay Leak Test for The 3.1 mbar maximum pressure above the maximum pressure drop Nonporous Flexible Packages with decay specification was established specification and failed the test. and without Restraining Plates (West with a 6σ interval of confidence for The method is, to the authors’ Conshohocken, 2001). PTE

Pharmaceutical Technology Europe JANUARY 2017 43 44 more of the principles of excellence, operational says Prabir Basu. consultant incorporate to need will they evolve, metrics quality pharmaceutical As Lab and the Plant Floor Joining the Quality Quality: Defining Agnes ShanleyAgnes Pharmaceutical Technology Europe F should drive, not only day-to-day operations, but also investment investment also but operations, day-to-day only not drive, should principles These quality. product determine that key principles on focus inspectors) plant (especially regulators and departments, control quality teams, manufacturing and operations process t t t following main three metrics: the on focuses (4), which guidance the of version asecond released 2016, FDA November In 10 metrics. for data collect manufacturers that asked FDA had scope. broad its about complaints were there testing. product final and (cGMPs) practices manufacturing good current of approach case-by-case the beyond get would that quality to approach asystemic for need the articulated which Q10 (2), Use’s (ICH) Human for Pharmaceuticals of Requirements Technical of Harmonization for Council International the of release the with 2008, in began (1). actually work This quality product to critical most are that indicators key performance and metrics the define to industry with working been has (FDA) Administration Drug  Invalidated out-of-specification (OOS) rate, or the number of OOS OOS of number the or rate, (OOS) out-of-specification Invalidated  complaints of number the or rate, complaint quality Product  within lots accepted of number the or rate, acceptance Lot  Long term, the agency’s goal is to furnish metrics that will help help will that metrics furnish to is goal agency’s the term, Long practices. best specifies guidance the and investigation, an trigger will result OOS Every frame. time the during facility the at performed tests such of number total the by divided facility, the at issues process measurement to due invalidated were that results test stability long-term and results test batch-release during distributed that timeproduct frame. that of units dosage of number total the by divided received rejected. and released, started, lots of number be will Included timeframe. agiven during packaging, and distribution secondary and primary for started, lots of number total the by divided a timeframe 2015 in (3), metrics quality on guidance initial FDA released After improve and sustain better product quality, and US Food the product better sustain and improve or the past few years, to help pharmaceutical manufacturers JANUARY 2017 PharmTech.com

due to the special requirements for for requirements special the to due insisting that “pharma is different,” excellence metrics, with some such universalmanufacturing embrace to reluctant been have improvement. quality total supports, management senior strongly how or in, engaged is workforce the maintenance, or how effectively predictive total uses company or facility the whether as things such operations lookmanufacturing at Gallen’s of pharmaceutical surveys St. levels. inventory and delivery” “on-time include which industries, automotive, aerospace, and other in used metrics universal the on based adecade, over well for manufacturingpharmaceutical Technology and Education (NIPTE). Institute for Pharmaceutical National the of head was 10 years, than more for who, Basu, Prabir consultant industry pharmaceutical States, United the in based and, Technology, led by Nuala Calnan, of Institute Dublin the from team a is Friedli with Collaborating industries. different across techniques improvement continuous of application the studying years 15 past the spent has who Friedli, Thomas by led Switzerland, in Gallen St. of University the at team (5). future in the results excellence might help achieve better operational of principles the and floor plant manufacturing the of language the of more incorporate whether new measurements that see to and metrics, quality existing research that aims to analyze risk of or quality compliance failure. highest the at are that companies toinspections focus on facilities and should help regulators prioritize they addition, In technology. new in excellence metrics. manufacturing universal such toembrace reluctant have companies been Some pharmaceutical Some pharmaceutical companies analyzing been has team Friedli’s a is project this on Working fund to 2016, FDA began July In

Tashatuvango/shutterstock.com Process Operations

product safety and testing. There Today, most manufacturing is Quality metrics has been debate over this topic for taking place outside of the US, PTE: How about the metrics that decades, and, even today, one sees and FDA has limited ability to FDA is focusing on in its latest uneven acceptance of such concepts inspect all the facilities involved. version of the draft guidance, as “process capability analysis” or Having indicators in place that are including out of specification? Are process analytical technology (PAT) operations related and that suggest these adequate? among drug manufacturers. which facilities and companies might Basu: The metrics are okay but pose a higher risk of noncompliance they aren’t yet tied to processes so or low quality will allow FDA to they won’t necessarily reflect what “The most important prioritize inspections. But it would is going on internally. For example, question is whether the be ideal if we could get to the stage lot acceptance rate seems okay, facility’s or company’s where quality and operational but what happens if lots have to processes are in a state of excellence are considered as one. be reworked? Will the figure then control. ” ICH Q10 gives us indications of how be a true reflection of the facilities’ — Prabir Basu to get there. processes? So, we are beginning a journey PTE: What are some concepts that has much potential, and we can that might be more helpful? At this point, FDA wants to see get to this goal of a unified definition Basu: I think that Six Sigma value whether the language of operational of quality, if we continue for the next could provide a better indicator. excellence can further enrich the three to five years. In the early 2000s, a number of industry’s understanding of quality. At this point, we are collecting thinkers used to talk about doing Research is still in a preliminary data using benchmarking this, but it hasn’t yet been fully stage, and could not be discussed questionnaires, correlating between accepted. for this article, but Prabir Basu existing operational excellence Even if we were to use the lot shared some of his thoughts on measurements and quality acceptance rate as a quality metric, what the industry will need if it metrics. We hope to expand the ideally some measure of accuracy is to redefine, and transform, questionnaire to reflect on real could be factored in, for example, of pharmaceutical quality control. quality information. the number of batches started, how many came out right the first time, Operational excellence without the need to rework them? PTE: Why is operational excellence “We need to come up PTE: What role should quality (OpEx) so important to improving with metrics that will complaints play? both pharmaceutical manufacturing be attractive for all Basu: This is an important metric, and quality? companies.” but first we need to define very Basu: Quality and operational — Prabir Basu clearly what the complaints are and excellence cannot be separated. where they are coming from. Are Operational excellence metrics they coming from the warehouse? show how motivated people within PTE: In the past decade, we’ve From distributors? From patients? a company are to improve overall heard more people in pharma talk From regulators? performance, and quality with it. about Deming’s approaches to Some of the metrics that are FDA has, in the past, taken an excellence, yet concepts as basic currently being discussed may approach that has separated the as process capability don’t seem to not adequately reflect internal two, as if quality were not a part have been widely embraced. Why is processes. The beauty of operational of operations. The point is, that if a that? excellence metrics is that they company is not investing in quality, Basu: Some companies are measure how well processes are that will show up in the operational working with the concept of performing, so they are much better excellence parameters, and they will process capability, but they tend reflections of the actual situation have quality problems too. to be the larger companies, such within a given facility or company. A great example is preventive as Amgen and Pfizer. And even the Some of the important operational maintenance. If you don’t have a larger companies don’t employ this excellence metrics to consider are corporate mandate and policy for approach for all products. on-time delivery and customer this activity, you are very likely to We need to come up with satisfaction. These measurements have problems with product quality. metrics that will be attractive for all reflect internal processes. PTE: How does all this affect companies. In addition, I believe that metrics regulators? PTE: How about cost of goods? must incorporate more of the Basu: Having links to existing Basu: That measure is too spirit of ICH Q10, to determine the OpEx quality parameters would be variable, because the cost of capital company’s quality culture, and very helpful in ensuring that FDA can varies so dramatically depending such things as whether the firm get pertinent information underlying on which country the facility or has a continuous improvement deviations or batch rejections. company is based in. program in place, whether its

Pharmaceutical Technology Europe JANUARY 2017 45 Process Operations

senior management is involved in of ICH Q9, etc. We need metrics to References quality, the degree of employee measure these areas, and also to 1. Measuring Pharmaceutical Quality involvement, and how the company identify facilities and companies through Manufacturing Metrics and prioritizes projects for improvement that are at the greatest risk of Risk-Based Assessment, Meeting (i.e., whether it uses ICH Q9 and quality and compliance failure. Summary, brookings.edu, May 2014, principles of risk assessment to help In the end, the number of www.brookings.edu/wp-content/ uploads/2014/05/Quality-Metrics- make those decisions). rejected batches may be more Meeting-Summary.pdf. important to screen than lot 2. ICH, Q10, Pharmaceutical Quality failures. In addition, relative “We need metrics to System (PQS), 2010, ich.org, www. numbers are more important than measure these areas, and ich.org/fileadmin/Public_Web_Site/ absolute numbers. For instance, the ICH_Products/Guidelines/Quality/ also to identify facilities top 25% should have good systems and companies that are at Q10/Presentation/Q10_General_ in place, and the bottom 25% should Presentation.pdf the greatest risk of quality receive more attention from FDA. 3. M. Mezher, “FDA Releases Long- and compliance failure.” It might be most beneficial to use Awaited Quality Metrics Guidance,” — Prabir Basu the pillars that St. Gallen has been raps.org., 28 July 2015, www. using to measure performance: total raps.org/Regulatory-Focus/ predictive maintenance, total quality News/2015/07/28/22939/FDA- The most important question is management, and just-in-time Releases-Long-Awaited-Quality- whether the facility’s or company’s inventory levels. Metrics-Guidance/. processes are in a state of control. Keeping a focus on process 4. FDA, Submission of Quality Metrics Data, Draft Guidance for Industry, Here, key indicators are measures operations will ensure that companies November 2016, FDA.gov, www. of variability of the critical process and regulators are monitoring fda.gov/downloads/Drugs/ attributes. Even if process operational principles, looking at GuidanceComplianceRegulatory capability information is not stabilizing systems, and developing Information/Guidances/UCM455957.pdf. available, at a minimum, trending of frameworks for knowledge 5. T. Friedli and P. Basu, “Measurement critical process variables and data management and risk management. of Pharmaceutical Quality in an on process drift such as shifting of By definition, these efforts can only Operational Excellence Environment,” the averages or changes in slopes of make any organization more focused in CPhI Annual Industry Report, 2016, the trend, degree of implementation on product quality. p. 15. PTE

CORRECTION Ad Index The API Synthesis & Manufacturing article, “New Horizons for Cross-Coupling Reactions” in the December 2016 issue COMPANY PAGE incorrectly stated: Capsugel ...... 33 Silicon-based cross-coupling reactions have recently been Catalent Pharma Solutions ...... 47, 52 shown to have potential advantages over existing cross- coupling chemistry, particularly with respect to alkyl-alkyl (sp3- Gerresheimer AG ...... 23, 47

3 3 2 sp ) and alkyl-alkenyl (sp -sp ) cross-couplings. Lonza Clinical Development & Licensing ...... 27

The correct statement is: Penn Pharma, A PCI Company...... 19, 48 Silicon-based cross-coupling reactions have recently been Rommelag AG...... 5, 48 shown to have potential advantages over existing cross- Schott AG ...... 2, 49 coupling chemistry, particularly with respect to alkyl-aryl and alkyl-alkenyl (sp3-sp2) cross-couplings, according to Gerald L. Shimadzu Europe ...... 51 Larson, a senior research fellow at Gelest. Starna Scientific ...... 9

A correct version of the article can be found in the TasiTest ...... 15, 49 digital edition: http://images2.advanstar.com/PixelMags/ UBMi BV ...... 41 pharma-tech-na/digitaledition/12-2016.html Unicom International ...... 31 Vectron Biosolutions AS ...... 11 Veltek Associates Inc ...... 7

46 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com PHARMAPACK EXHIBITOR PROFILES

Catalent Pharma Solutions

Company multiple answers throughout a product’s provides not only the capacity to support description lifecycle, Catalent can improve the total partners, but also access to specialised Catalent Pharma value of treatments, and accelerate technologies that ensure extreme Solutions is the programs to the clinic and beyond. precision for safer, more accurate dosing. leading global Its expertise in process design, scale-up, provider of Catalent. More products. Better quality assurance, validation and regulatory advanced delivery treatments. Reliably supplied.TM support provides efficiency and support technologies and across virtually any sterile dosage form. development Major products/services solutions for drugs, being exhibited biologics and Catalent’s prefilled syringes provide both consumer health safety and convenience advantages over products. multi-dose forms. With more than From its sites in Europe, Catalent has over 80 years’ experience across prescription 80 years’ experience in providing specialised Contact details and consumer markets, Catalent has the scientific and manufacturing of complex Catalent Pharma Solutions deepest expertise, the broadest offerings, injectable treatments. As a market leader 14 Schoolhouse Road and the most innovative technologies, to in sterile manufacturing, Catalent offers an Somerset, NJ 08873 USA help its customers get more molecules extensively customisable range of prefilled Tel. +800 88 55 6178 (EU) to market faster, enhance product syringe products alongside innovative +1 888 765 8846 (USA) performance, and provide superior, fill-finish processes, and speciality delivery [email protected] reliable manufacturing and packaging vehicles such as auto-injectors. www.catalent.com results. With an annual syringe-filling capacity From a single, tailored solution, to of more than 200 million units, Catalent Booth A80

Gerresheimer

and South America, and Asia generating The product highlights: revenue in excess of EUR 1.4 billion. The t Tungsten-free 1 ml long Luerlock Gx comprehensive product portfolio includes RTF syringe premieres at Pharmapack pharmaceutical packaging products as t Multilayer Containers for Solid Dose well as convenient and safe drug-delivery Medications systems such as insulin pens, inhalers, t High Quality Primary Packaging pre-fillable syringes, vials, , t Customer-specific Drug Delivery bottles, and containers for liquid and solid Systems, Medical Devices and pharmaceuticals with closure and safety Diagnostics Products systems, plus products.

Major products/services being exhibited Gerresheimer will have a range of new Company description products and solutions for safe, reliable, Gerresheimer is a leading global partner and convenient pharmaceutical drug Contact details to the pharma and healthcare industries. packaging and delivery on show at Gerresheimer The company’s special glass and plastic the 20th Pharmapack. A Gerresheimer 40468 Düsseldorf products contribute to health and product expert will also be making Tel. +49 211 6181-0 well-being. Gerresheimer is a global a presentation on the production of Fax: +49 211 6181-295 organization with 10,000 employees and multilayer plastic containers in an [email protected] manufacturing operations in the local injection blow moulding process for the www.gerresheimer.com markets, close to customers. It has over reliable protection of content against 40 production facilities in Europe, North water vapor and oxygen exposure. Hall 4, Booth G1/H1

Pharmaceutical Technology Europe JANUARY 2017 47 PHARMAPACK EXHIBITOR PROFILES

PCI Pharma Services

supporting lifesaving medicines destined to brought the need for serialization to the over 100 countries around the world. forefront of the healthcare packaging With over four decades of commercial market. PCI offers a robust set of pharmaceutical packaging expertise serialization services. and in excess of 50 successful product launches per year, PCI is a trusted Major products/services Company description leader and industry expert in the being exhibited PCI Pharma Services is an integrated full commercialiation of new medicines. Commercial pharmaceutical packaging service provider, a proven and trusted Our global capabilities include expertise, Serialisation, Anti- partner to leading companies in the global packaging for large-scale projects counterfeiting and Tamper Evident healthcare industry. We offer unparalleled requiring sophisticated integrated Solutions, Commercial Launch expertise and experience in taking technologies and automation and the compounds from the earliest stages support of more targeted therapies for of development through to successful select patient populations. commercialization, delivering speed-to- PCI partners with clients to develop market and commercial success for our dynamic and multi-faceted strategies Contact details customers. for ensuring product integrity, utilizing PCI Pharma Services Our core services support each the latest technologies in product Wye Valley Business Park, stage of the product lifecycle, including serialization and cutting edge solutions Hay-On-Wye, HR3 5PG, UK drug development, clinical trial supply, for incorporating anti-counterfeiting Tel. +44 (0)1497 820829 commercial launch and ongoing commercial requirements for packaged products. [email protected] supply. We partner with clients in providing Evolving legislation within the United www.pciservices.com innovative technologies, flexible solutions, States and European Union, along with and an integrated supply network a patchwork of global requirements, has Booth H79

Rommelag CMO, works Holopack Verpackungstechnik GmbH

whether you’re looking for help with trial Non-GMP-Products batches, the development phase (including t Cosmetics feasibility studies, stability tests, and t Food supplements clinical samples) or getting batches ready for market, we’ve got it all covered. Technical Products t Pheromones Major products/services t Machine oil and Motor oil t Detergents Company description being exhibited Rommelag CMO provides you with quick We are able to fill the following applications: and easy access to BFS technology without Drugs and Medical devices having to invest in either the mandatory according to GMP GMP environment that goes with it or the t Eye, ear, and nasal drops specialists required to operate and maintain tHomeopathy the machines. What we offer is the whole t Inhalations Contact details spectrum, including the entire infrastructure t Infusions and injections Rommelag CMO, works Holopack itself, over 50 years’ experience in bottling tRinsing solutions Verpackungstechnik GmbH using BFS aseptic systems, and the tOrals Bahnhofstrasse 18, expertise you’d only get from the inventors t Cremes, ointments, and gels 74429 Sulzbach-Laufen, of bottelpack technology. tWound care products Germany With over 50 systems in a whole host t Vaginal applications of different configurations, Rommelag t Rektal applications Tel. +49 7975 960-0 CMO runs one of the world’s largest, t Disinfectant solutions Fax. +49 7975 960-411 most state-of-the-art bottelpack system t Diagnostika [email protected] ranges. It goes without saying, we’re t Biologicals www.rommelag.com ideally placed to meet your bottling needs t Vaccines in no time at all and at minimum cost. So t Biotechnological products Booth G38

48 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com PHARMAPACK EXHIBITOR PROFILES

SCHOTT AG

meet growing market demand from drug glass is collected online and in manufacturers. The latest nest format real-time – an innovation that sets new will be able to hold 20R, 25R, or 30R ISO standards in the pharmaceutical glass vials when it’s released in 2017, and will industry. add to the existing 2R to 15R formats. The adaptiQ® concept permits pharma firms to fill different container formats on one production line while minimizing burdensome changeover times in Company description between. SCHOTT developed adaptiQ® to SCHOTT is one of the world’s leading be compatible with the industry’s filling suppliers of pharmaceutical tubing and finishing equipment, and collectively, and parenteral packaging for the industry leaders such as Bausch & pharmaceutical industry. More than Stroebel, Bosch Packaging Technology, 600 production lines in 13 countries Groninger, Optima, and Vanrx have tested Contact details worldwide produce more than 10 billion and verified adaptiQ on a large number of SCHOTT AG syringes, vials, ampoules, cartridges, and machine types. Hattenbergstrasse 10, special articles of tubing glass or polymer. SCHOTT is also integrating a specially 55122 Mainz, Germany Furthermore, the company produces over developed big data solution into its Tel. +49 (0)6131/66-1589 150,000 tons of glass tubing each year. pharmaceutical tubing production, pharmaceutical_packaging@ replacing statistical sample-based quality schott.com Major products/services assurance with 100 percent on-line www.schott.com/pharma, being exhibited measurement. With the new IT-based www.schott.com/perfexion SCHOTT has expanded its portfolio of process called perfeXion™, process- and ready-to-use pharma containers to product-quality data of each individual Hall 4, Booth F1 & H89

TASI TEST - Sepha Standard Solutions /ADMC

Company description suitable for inline, diagonal and offset Specialised pharmaceutical Sepha Standard Solutions is a layouts in addition to small-scale blister equipment for Package and Closed pharmaceutical engineering company packing machines ideal for R&D, product Container Integrity Testing, Product specialising in the manufacture of tool- development and clinical trials. We work Recovery and Blister Packaging. Testing less non-destructive package integrity with the majority of the world’s top services and Blister design services also test equipment for a wide range of pharmaceutical companies and are part available. products including blister packs, of the global Test and Inspection leader, induction-sealed bottles, sachets, TASI Group. pouches and medical device packaging. We also provide a comprehensive Major products/services range of automatic, semi-automatic being exhibited and manual deblistering machines Leak detection services

Contact details TASI TEST - Sepha Standard Solutions /ADMC Unit 25 Carrowreagh Business Park, Dundonald, Northern Ireland BT16 1QQ Tel. 02890 484848 Fax. 02890 480890 [email protected] www.tasitest.com

Booth L63

Pharmaceutical Technology Europe JANUARY 2017 49 ASK THE EXPERT

Staffing and Preparation for Audits

Siegfried Schmitt, PhD, principal consultant, PAREXEL, discusses how to handle audits and inspections during business expansion.

Our quality unit is responsible for hosting audits and This playbook can be in any format suitable for your needs, Q:inspections for our manufacturing site. We are a contract but often it is in the form of a spreadsheet. A spreadsheet manufacturer and due to our expanding client base, we are allows activities to easily be added into sequence and experiencing a growing number of customer audits and regu- the ability to select tasks for individual roles or locations. latory inspections. Can you provide advice for how to best Furthermore, completed tasks can be ticked off, together with accommodate this increased workload? any comments or feedback as required.

First, congratulations on your growing business. In Information for auditors A:terms of managing this rising number of audits and A number of documents and data are typically requested by inspections, we would recommend developing procedures. auditors and inspectors; including, but not limited to: Formalized processes, in addition to using the right tools, can t Number of deviations help make the job more predictable, improve planning, and t Number of batches manufactured provide a higher chance of success. You may call this a play- t Number of out-of-specification (OOS) results book, or simply “Good Guide to Audits/Inspections.” Being t List of standard operating procedures (SOP) prepared and having a defined process helps reduce uncer- t Organizational structures tainty and drives efficiency. t Annual quality reports t Number of complaints t Number of recalls (if applicable). Having a spreadsheet to refer back to, therefore, is crucial Being prepared and having to staying organized and up to date with inspections. Having a running tally readily available in electronic format will greatly a defined process helps reduce the effort with preparations. It can also be beneficial to keep a set of printed copies of all SOPs handy, making these reduce uncertainty and available upon request, which reduces time and effort during drives efficiency. the audit or inspection. Being prepared is key Ultimately, the key to being prepared for audits and It is good practice to start putting together this document by inspections is to follow the old adage: preparation, preparation, getting input from all parties involved. We recommend starting preparation. Furthermore, with practice comes experience, at the moment an audit or inspection is announced, and then and with experience comes perfection. Maintaining structuring it by phase, such as preparation/planning, hosting, procedures and metrics will be helpful for any inspection, follow up/post event, and close out. especially as you expect to experience more inspections due The guide should include roles, rather than name-specific to a growing client base. PTE individuals, when explaining responsibilities involved in the inspection, as this eliminates the need for many updates or changes. For each role, it is beneficial to describe each person’s particular involvement in the inspection (e.g., active or stand by/back up), what and when they are needed, where Your opinion matters. (e.g., front office or back office “war room”), and any other Have a common regulatory or compliance question? pertinent information. Note that some roles may only be Send it to [email protected] and it may appear in a future column. required occasionally, such as translators.

50 Pharmaceutical Technology Europe JANUARY 2017 PharmTech.com Combined forces Nexera MX and LCMS-8060: ultra-fast multiplexing UHPLC meets ultra-trace level detection

The Nexera MX ultra-fast multiplexed UHPLC system combined with Unmatched speed the LCMS-8060 triple quadrupole mass spectrometer provides routine with fastest sample injection, data acquisition and polarity switching high performance LC-MS/MS analysis that makes a real difference in time increasing laboratory efficiency. Nexera MX features two analytical flow lines in a single UHPLC system; this doubles sample processing Dedicated software packages capability when compared to the conventional single channel approach. for automated method and batch creation as well as simplified data The LCMS-8060 adds ultra-fast polarity switching and scanning speed, evaluation highest sensitivity and robustness to push the limits of LC-MS/MS quantitation.

Boosted operating efficiency through multiplexing technology

www.shimadzu.eu/nexera-mx Nexera MX and LCMS-8060 sterile technologies

advasept® technology glass-free injectable delivery. automated aseptic. reliably supplied.

Our next generation glass-free injectable platform, with advanced aseptic filling technology, has the potential to reduce foreign particulates by more than 95%, increase sterility assurance through automation, and improve supply reliability.

Catalent. More products. Better treatments. Reliably supplied.™

˝ 2016 Catalent Pharma Solutions. All rights reserved. ˝ 2016 Catalent Pharma Solutions. All rights reserved. us + 1 888 SOLUTION (765-8846) eu + 800 8855 6178 catalent.com/advasept