Glycosylation Supply Chain Good Laboratory JUNE 2019 Volume 43 Number 6

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Pharmaceutical Technology is the authoritative source of peer-reviewed research

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development, manufacturing, formulation and drug delivery, API synthesis, analytical
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COVER STORY
cover
the cover

16 Putting Drug Delivery

Into Patients’ Hands
n the

Wearable and smart devices allow

user-friendly subcutaneous drug delivery.

Cover Design by Dan Ward

On

Images: Korn V./nikilitov - stock.adobe.com

O

F E ATURES
FEATURES
API SYNTHESIS & MANUFACTURING SCALE UP SUPPLY CHAIN

20 Enabling Technologies 29 Batch or Continuous? 44 On the

Advance Poorly Soluble Ask the Right Questions Right Track
Highly Potent APIs During Scale Up Proactive approaches that
Excipients and new processing Continuous manufacturing consider long-term supply
techniques can make a real may offer huge opportunities, chain security compliance
difference in the development but it will not be right for are recommended to ensure
of highly potent therapies. every facility or product. companies stay on the right track.

FORMULATION ANALYTICS GOOD LABORATORY PRACTICES

24 Looking Beyond 40 Leveraging Computational 47 Good Laboratory

the Solubility Horizon Models of Glycosylation Practices: Getting on

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Exploration of various formulation for Biopharma QA the Same Page
techniques is vital to provide effective Close collaboration between academic Quality and compliance depend on the
delivery of poorly soluble drugs. and industrial groups is vital to ensuring right approaches to training, standard
glycosylation models are fit for deployment. operating procedures, and validation.
INHALATION DRUG MANUFACTURING

27 Considering Connected Continued on page 8

Inhalation Drug Delivery
A connected MDI may encourage
compliance and aid proper technique.

PEER-REVIEWED RESEARCH
PEER-REVIEWED

32 Defining and Managing Raw Manufacturing Data

Protecting the integrity of raw data is crucial to regulatory compliance and to
proving that manufacturing and quality operations are being run and managed properly.

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Continued from page 6

NEWS & ANALYSIS REGULATION & DEPARTMENTS/

FROM THE EDITOR COMPLIANCE PRODUCTS
10 Pharma REGULATORY WATCH 12 Product Spotlight
Facilities Still Have 14 FDA 49 Marketplace
a Lot to Learn Advances New
FDA’s annual manufacturing report card Approach to Drug
49 Ad Index
shows more quality compliance is needed. Quality Assessment
CDER’s KASA program seeks
manufacturer data on drug attributes
and risks to inform oversight.

ASK THE EXPERT

50 Quality Agreements
and Out-of-Specification
Investigations
A good working relationship between
sponsor and contractor will become
invaluable when an OOS occurs, says
Susan J. Schniepp, executive vice-president
of post-approval pharma and distinguished
fellow, Regulatory Compliance Associates.

PHARMACEUTICAL TECHNOLOGY (Print ISSN: 1543-2521,

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from the editor

Pharma Facilities
Still Have a Lot to Learn
Rita Peters

FDA’s annual manufacturing report card

shows more quality compliance is needed.

A
s schools in the United States close peutic category, application type, and Less than 40% of the drugs for the
for the summer break, student manufacturing sector. FDA issues a site US market are manufactured in the US;
grades serve as a measure of how inspection score—on a scale of 1 to 10 India (12%) and China (11%) are the
well teachers shared knowledge, how well with a higher number indicating greater two largest offshore suppliers. FDA also
students understood and retained that compliance with current good manufac- noted that a small number of sites manu-
information, and how the school, as a turing practices—based on FDA quality facture a large number of listed products;
whole, performed this year. inspections over the past 10 years. the number of products manufactured at
FDA recently issued a report card of The number of sites in FDA’s site a site is a risk factor used in prioritizing
the bio/pharma industry’s manufactur- catalog—4676 at the end of FY2018— the need for surveillance inspections. In
ing quality performance, which provided needs some clarification. Of the total the US, three sites—two of which make
insight on how well manufacturers and sites in the catalog, 42% manufac- homeopathic products—account for
regulatory authorities executed their re- ture “no application” products, such 9.5% of all products listed by all US sites.
sponsibilities, and lessons learned for fu- as over-the-counter products, mono- The number of listed products manu-
ture improvements. graph, unapproved, or homeopathic factured by the top three sites in China
The Report on the State of Phar- products. The remaining 58% of (11.2%) and India (12%) are even higher.
maceutical Quality (1), issued in May sites manufacture application drug
2019 by the Office of Pharmaceuti- products (e.g., new drug application Inspections and grading
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cal Quality in FDA, Center for Drug
Evaluation and Research, assessed the
[NDA], abbreviated new drug appli-
cations [ANDA], biologic license ap-
In FY2018, FDA conducted 1346 drug
quality inspections, covering less than
ability of pharmaceutical manufactur- plication, etc.) and nearly half (46%) one-third of sites in its catalog; more
ers to deliver quality pharmaceutical of these sites manufacture both NDA than half of the inspections were outside
products to the US market during and ANDA products. the US. The average inspection score of
fiscal year 2018. The report analyzed The report noted “volatility” in the site 7.5 for FY2018 was down slightly from
product recalls, quality defect reports, catalog in the past year; the agency re- FY2017 (7.7). Sites in the European Union
drug shortages, and application state moved from the catalog “a large number” (7.9) and the US (7.7) scored higher than
(e.g., submissions, approvals, refuse- of sites in India, China, and South Korea average; sites in China (7.0), India (7.0),
to-file, refuse-to-receive, and com- in FY2018 because they did not make and the rest of the world (7.2) were lower
plete response letters) as a basis for products for the US market and, there- than average. Statistical differences were
its analysis. fore, did not have to be registered with also noted in application areas, with ster-
FDA. The need to purge manufacturing ile non-application products as one of the
Site report card sites from the list indicates “a lack of un- lowest performing.
The report examined manufacturing derstanding of the registration and listing FDA noted “… some trends highlight
site data by geographic region, thera- requirements,” FDA noted in the report. opportunities for increased outreach
PATPITCHAYA/SHUTTERSTOCK.COM

The data also show shifts in the types to, surveillance of, and enforcement
of site registrations. FDA reported a 32.8% of certain markets,” indicating that for
net increase in the number of packaging regulated drug manufacturing, school
and labeling sites—suggesting an increase is never out.
Rita Peters is editorial in outsourcing of these functions. In addi-
director of Pharmaceutical
Technology. Send your
tion, there was a 29.7% net increase in the Reference
thoughts and story ideas to number of “no application” sites and a net 1. FDA, Report on the State of Pharmaceutical
[email protected]. loss in the number of NDA sites. Quality, May 13, 2019. PT

10 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m

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regulatory watch

FDA Advances New Approach

to Drug Quality Assessment
Jill Wechsler

CDER’s KASA program seeks manufacturer data

on drug attributes and risks to inform oversight.

A
s part of its ongoing efforts to for ways to evaluate submissions more formation and “minimizes text-based
ensure the availability of high- expeditiously and effectively. This narratives,” explained OPQ Deputy
quality medicines, FDA’s Center new approach asks manufacturers to Director Lawrence Yu. Advances in in-
for Drug Evaluation and Research file structured applications that pres- formation technology not only gener-
(CDER) is rolling out a new system to ent key data on product attributes, as ate more information on key quality at-
enhance the evaluation of prescrip- opposed to lengthy, text-based narra- tributes, Yu pointed out, but also allow
tion drug attributes, risks, and control tives. The aim is for OPQ staffers to for a faster, more complete assessment.
strategies. The Knowledge-aided As- perform computer-aided analyses that He directed manufacturers to an ar-
sessment and Structured Application support benefit/risk assessments for ticle outlining the KASA program in
(KASA) initiative aims to improve the International Journal Of Pharma-
the efficiency, consistency, and ob- ceutics: X for further information on
The KASA initiative
jectivity of regulatory quality assess- the program and its approach (2).
ment by collecting structured data on Similarly, at the April 2019 CMC
aims to improve
drug substance, product design, and Workshop sponsored by the Drug In-
the efficiency,
manufacturing process to better as- formation Association (DIA), Geoffrey

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sess inherent risks and how they are
consistency,
controlled. CDER’s Office of Phar- and USE Wu, associate director of OPQ’s Office
of Lifecycle Drug Products (OLDP),
maceutical Quality (OPQ) is piloting described how the KASA initiative
objectivity of
the program first for abbreviated new will capture and manage knowledge
drug applications (ANDAs) for gener- of drug product quality to establish
regulatory quality
ics, with the aim of rolling out the sys- a product risk control strategy for
tem to generic solid oral dosage forms lifecycle management. This approach
assessment.
by year-end. Next will come generic will avoid inconsistent application of
liquids and injectables, followed by quality standards and help prevent
new drugs and biologics. comparison across products and fa- shortages and quality failures of mar-
With more ANDAs and new drug cilities. Under development for almost keted drugs. KASA also will assess
applications (NDAs) filed each year, two years, the KASA initiative became manufacturing risks and controls in
many involving complex therapies, more visible when it was discussed pub- order to “flag the potential need for a
and increasingly tight assessment time licly and gained unanimous support at pre-approval inspection based on mul-
frames for approval set by user fee the September 2018 meeting of FDA’s tiple factors and complexities using
programs, CDER officials are looking Pharmaceutical Science & Clinical standardized risk thresholds,” Wu
ORHAN CAM/SHUTTERSTOCK.COM

Pharmacology Advisory Committee. noted. This will involve examining

CDER and OPQ leaders presented the control strategy for the manufac-
more detailed information on KASA turing facility, including site inspec-
at the April 2019 PQRI/FDA confer- tion history, based on a standardized
Jill Wechsler ence on Advancing Product Quality assessment of risks compared across
is Pharmaceutical in Rockville, MD (1). KASA aims to products and facilities.
Technology’s
Washington editor, provide a structured assessment of an
[email protected]. application that summarizes key in- contin. on page 38

14 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m

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Cover Story: Drug Delivery Devices

Putting Drug Delivery

Into Patients’ Hands
Jennifer Markarian

Wearable and smart devices allow user-friendly subcutaneous drug delivery.

T FOR PERSONAL, NON-COMMERCIAL USE

he trend to self-administered, home-says Ian Thompson, vice-president of cosities or fill volumes. This drive system
based, subcutaneous drug delivery isbusiness development at Ypsomed De- ensures consistent flow rates, which allow
creating a need for drug-device com-livery Systems. “We believe the key ap- reproducible injection times, and the elec-
bination products that are easy to use cor-
plications for patch injectors will be in tronic circuitry is already in place to pro-
rectly and designed with patients in mind.
the 3–10 mL space for monthly or quar- vide connectivity. The devices are designed
Patients may be familiar with prefilled, terly autoimmune or immuno-oncology to hold standard, 10-mL glass cartridges
handheld autoinjectors or pens. Another therapies,” he notes. Ypsomed is develop- that are filled in a ready-to-fill tub format.
type of device, not as familiar today buting YpsoDose as a prefilled, ready-to-use, Sorrel Medical is developing single-use,
perhaps soon to see broader use, is the patch injector for antibody-based drugs prefilled wearable injectors in configura-
wearable autoinjector, which is attached to
in the range of 3–10 mL (see Figure 1). tions ranging from 1–20 mL. “The 3-mL
the skin to inject a larger volume dose over
Functional devices for testing are avail- device configuration has been fully verified
a matter of minutes, compared to seconds able, and the company is engaging in and validated and is available for perform-
for the smaller dose of a handheld injector.
feasibility trials with pharma companies, ing feasibility testing by our pharmaceuti-
The increasing use of biologics that must be
says Thompson. cal partners,” says Andrei Yosef, CEO of
delivered in larger-volume doses is creatingUsing platform technologies that can Sorrel Medical. “The 20-mL device has
a growing need for these larger-volume, be easily customized for multiple thera- working prototypes available. The other
KORN V./NIKILITOV - STOCK.ADOBE.COM

wearable autoinjectors, which may also bepies is important for manufacturing cost- configurations are in the earlier stages
called patch injectors, large-volume bodyefficiency, which is particularly important and can be developed to commercializa-
injectors, on-body delivery systems, or for drugs that target smaller patient popu- tion with a partner.” Yosef notes that all the
wearable bolus injectors (WBIs). lations and thus have low annual quanti- devices are based on the same pumping
ties, notes Thompson. Ypsomed produces mechanism, with slight modifications to
New device platforms devices for multiple products and custom- the outer shelling to accommodate differ-
Choosing a wearable injector rather than ers from the same tooling and equipment. ent sized primary containers. Using a plat-
a handheld injector depends on the in- In addition, the electromechanical drive form solution lowers risk in development
jectable volume and injection frequency, system is programmable for different vis- and commercialization, adds Yosef.
16 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
 Impact of New FDA Guidance
on Bioanalytical Testing
on Drug Development
ON-DEMAND WEBCAST Aired May 30, 2019

Register for this free webcast at www.pharmtech.com/pt_p/guidance

EVENT OVERVIEW: Who Should Attend

In this webcast, learn how the FDA Bioanalytical Method ■ Pharmaceutical and biopharmaceutical industry
CEOs, directors, and scientists who are decision
Validation Guidance (May 2018), the FDA Immunogenicity
makers within their companies and individuals
Testing of Therapeutic Protein Products (January 2019), and the who outsource bioanalytical to CROs
February 2019 draft International Conference on Harmonisation
(ICH) Bioanalytical Method Validation M10 guidelines have
Presenters
changed or are poised to change the landscape of outsourc-
Franklin Spriggs
ing bioanalysis to support drug development. Additionally, the Director, Biopharmaceutical
webinar will cover gaps in bioanalytical method validation guid- Services
ance to support drug development most notably flow cytometry KCAS Bioanalytical
support of gene therapies. and Biomarker Services

The webcast will highlight the areas of each guidance that Marsha Luna

FOR PERSONAL, NON-COMMERCIAL USE

indicate a change of thinking from previous documentation Director, Pharmaceutical
provided by the agency. Experts will discuss the practical side of Services
KCAS Bioanalytical
execution of these updated parameters, where appropriate, and and Biomarker Services
the impact the documents will have on the scope and time line
for outsourcing of bioanalytical analysis. Stephanie Bull, RQAP-GLP
Key Learning Objectives Quality Assurance Team Lead
■ What is new in FDA’s May 2018 Bioanalytical Method Validation KCAS Bioanalytical
Guidance? and Biomarker Services
■ What is new in FDA’s January of 2019 Immunogenicity Testing of
Therapeutic Protein Products?
Moderator
■ What is new in the February 2019 draft of the ICH Bioanalytical Method
Validation M10 guidelines? Rita Peters
■
Editorial Director
What actions should bioanalytical testing labs take to adapt to these
new guidelines? Pharmaceutical Technology

Sponsored by Presented by

For questions contact Martha Devia at

[email protected]
Cover Story: Drug Delivery Devices
Figure 1. Ypsodose is Ypsomed’s by using a standard glass cartridge with a give manufacturers the ability to improve
3–10-mL prefilled, preassembled plunger of standard material. the design of wearables. Customized de-
patch injector. The enFuse On-Body Infusor from signs could reduce the container size to
Enable Injections, shown in Figure 2, is make the device more discreet, for ex-
being developed as a device platform for ample, or add dimensional features (e.g., a
volumes from 5–50 mL, says Matt Hud- ring, bar, or notch) to the container to im-
dleston, Enable Injections executive vice- prove alignment and allow easier assembly
president and chief technology officer. A or improve the connection force between
unique aspect of the technology is the use the container and device, explains Tom
of a constant-pressure design using an van Ginneken, global product manager at
elastomeric pump, rather than a constant- SCHOTT. Such containers would use stan-
flow design using an electromechanical dardized tub-and-nest transport packag-
pump. “This design allows the enFuse to ing for the filling step.
Figure 2. The enFuse On-Body Infusor automatically adapt to the injection site
from Enable Injections is being back pressure, and it is hypothesized to Smart and connected devices
developed as a platform for volumes potentially alleviate infusion site leakage The move to self-administration at home
from 5–50 mL. and pain,” notes Huddleston. The com- rather than in a clinic makes communicat-
pany received a US patent in March 2018 ing information to patients crucial. Devices
for its expandable elastomeric bladder and designed for self-injection can incorporate
infusion cannula system, and additional “smart” sensors and mechanisms to com-
patent applications are pending in the municate information from the device to
United States and other countries. Apel- the user. Furthermore, wearable injectors
lis Pharmaceuticals is conducting human can be connected through the Internet,
clinical trials using enFuse technology to typically using near-field connectivity
deliver its immunotherapies, and bio- (NFC) or Bluetooth, to communicate in-
pharmaceutical company UCB entered formation through a smart phone or other
a development agreement with Enable connected device to a patient or to others,
Injections in November 2018 (1). such as their medical team.
West’s SmartDose technology platform On Sorrel Medical’s devices, for ex-
(see Figure 3) is an on-body infusor that ample, smart sensors “include air and oc-
uses a Daikyo Crystal Zenith cartridge clusion detection, needle position, ensur-

FOR PERSONAL, NON-COMMERCIAL USE

Subcuject is developing a platform for and a Flurotec-coated piston contain- ing the primary container is in place, and

FIGURE 1 IS COURTESY OF YPSOMED DELIVERY SYSTEMS; FIGURE 2 IS COURTESY OF ENABLE INJECTIONS.

prefilled WBIs to deliver 1–10 mL of drug ment system. A combination product on-body detection, in addition to a series
using an osmotic pump, which is a fully from Amgen for a single, monthly dose of internal system checks,” says Yosef. In
mechanical drive, without electronics. “Os- of Repatha (evolocumab) using West’s addition, Sorrel’s devices have integrated
mosis can create a high drive pressure and SmartDose technology was approved NFC and Bluetooth connectivity.
it is, therefore, not a problem with high vis- by FDA in July 2016 (2). In January 2019, In the enFuse device, a gauge and the
cosities or high tissue back pressure, which scPharmaceuticals announced that it had button mechanism give active feedback
can be a problem with electromechanical completed preliminary feasibility stud- to the patient for delivery progress and
devices. The injection flow rate is around ies of its Furoscix (furosemide) with the end-of-delivery cues, says Huddleston.
1 mL per minute for viscosities up to more SmartDose Drug Delivery System and “Beyond this, an option in development
than 50 cP,” explains Jesper Roested, CEO was moving forward with development for connectivity will be capable of inter-
of Subcuject. Eliminating the electronic in anticipation of filing a new drug appli- facing with smartphone applications to
component also eliminates the limitations cation in 2020 (3). West also announced give information such as the delivery sta-
of battery life in cold storage conditions a collaboration with fill/finish provider tus of the device and the patient,” he adds.
and reduces the environmental impact of Swissfillon, to provide bio/pharma cus- “Connectivity could potentially improve
disposal, he says. The company is currently tomers with clinical fill/finish capability patient compliance, verify proper device
testing performance of functional device with the SmartDose technology (4). function, and increase patient safety by
models, and the device is expected to be identifying possible risks.” Management
ready for regulatory development by the Primary container design of confidential patient data, however, is a
beginning of 2020. The WBI is designed Most wearable injectors are designed to use challenge, and connectivity to a health-
to have low cost of goods, and assembly conventional primary containers. A new care provider or other party can raise
and filling is straightforward, says Roested. development program from SCHOTT is concerns about data privacy.
It is also designed to promote uncompli- aimed at bringing design freedom to the “Both pharmaceutical companies and
cated development at pharma companies container, which the company says can device manufacturers are aware of the
18 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
 Figure 3: West’s SmartDose platform includes devices with dose volumes of up to 10 with medical-grade quality components,
mL and preloaded options. dual-sourcing components where feasible,
and understanding the total cost of supply
are key considerations.
Finding manufacturing efficiencies
such as using automation or standard
parts (e.g., electronic chip or Bluetooth
module) will be important for bringing
down the cost of connected products,
agrees Jansen. Another challenge is ensur-
ing the electronics and software are com-
pliant, including testing for data security
vast potential in having data from con- member. “Initial products are expected and understanding and minimizing the
nected drug delivery devices, and how it to be focused on clinical trial use. In this risk of software bugs. Managing software
may be utilized to benefit various patient environment, patients are engaged and updates can also be a challenge. “Pharma
populations,” agrees Yosef. “We believe motivated to collect data,” notes Jansen. companies should be prepared for the
the question of how that data will be Connected devices are ideal tools for unique challenges of being accountable
used is one that must be had with each disease management, says Sai Shankar, for connected products,” Jansen says.
individual pharmaceutical partner based vice-president, Global Digital Healthcare
on the molecule, the indication, and the Systems, at Aptar Pharma, which offers References
patient population.” both add-on and integrated connected 1. Enable Injections, “Enable Injections Enters
Connected devices are being devel- devices for several different delivery into Strategic Partnerships with UCB and
Apellis Pharmaceuticals,” Press Release,
oped for combination products besides routes. “They provide real-time analysis
Nov. 13, 2018.
wearable injectors. For example, Hasel- of dose adherence and patterns of dose 2. West, “West’s SmartDose Drug Delivery
meier is collaborating with Common administration, and they are potentially Technology Platform Selected by Amgen
Sensing to develop a smart, disposable in- diagnostic tools to assess patient health for Pushtronex System,” Press Release, July
jector pen platform. Haselmeier’s subcu- and potential exacerbations.” Although 11, 2016.
taneous drug delivery injection systems the initial cost may be a concern, Shankar 3. scPharmaceuticals, “scPharmaceuticals Inc.
Announces Development Agreement with
for self-administration will be combined believes that the cost of connected devices
West Pharmaceutical Services for Next-
with Common Sensing’s Gocap injector will come down as increased adoption re- Generation FUROSCIX On-Body Infusor,”
monitoring technology to record the time sults in higher volumes. A key challenge Press Release, Jan. 29, 2019.

FOR PERSONAL, NON-COMMERCIAL USE

and amount of every injector dose, along
with other information, such as storage
for manufacturing connected devices is
managing the need for manual assembly of
4. West, “West and Swissfillon to Partner on
an Integrated Solution for Clinical Filling of
SmartDose Drug Delivery Platform,” Press
temperature, says the company (5). Ini- early-stage, low-volume devices as well as
Release, Feb. 6, 2019.
tially the monitoring cap will be an add- the need for automated assembly for higher
5. Common Sensing, “Haselmeier and Com-
on, replacement cap, but is intended to volumes, he notes. Securing the supply mon Sensing Enter Connected Injectable
eventually be an integrated device, says chain for electronic components is crucial, Medicine Collaboration,” Press Release,
Paul Jansen, Haselmeier advisory board adds Shankar. Selecting known suppliers May 3, 2018. PT

Human factors engineering

Developers of drug-device combination products should use human factors part. Without demonstrating that appropriate mitigations have been put in
(HF) studies to ensure that the product can be used effectively and safely place to resolve these types of use errors, substantial design changes to the
and “eliminate or mitigate patient adverse events and medication errors device constituent part may be required to gain product approval.”
attributable to use-related errors” (1). Failure to adequately integrate the drug and device constituent parts within the
“Human factors engineering (HFE) studies are not a ‘check the box’ activity overall design and development plan for the drug-device combination product is
to meet submission requirements,” says Stefanie Johns, Enable Injections another problem, says Johns. “The bottom line is that drug and device constituent
associate director of Regulatory Affairs. “Complete response letters for drug- parts cannot be developed independently or in silos; cross-functional team
FIGURE 3 IS COURTESY OF WEST

device combination products are most frequently a result of HFE deficiencies. members from both sides must communicate frequently and transparently.”
It is up to the marketing application holder to demonstrate safe and effective
Reference
use of the drug-device combination product by the intended users within the 1. FDA, Human Factors Studies and Related Clinical Study Considerations in
intended use environments. The HFE deficiencies identified by FDA during Combination Product Design and Development, Draft Guidance (Feb. 2016).
review are often related to concerns that specific use errors identified in HFE
studies may lead to a potential underdose or overdose of the drug constituent —Jennifer Markarian

Pharmaceutical Technology JUNE 2019 19

API Synthesis & Manufacturing
have permeability that is limited due their
larger sizes, according to McNaughton.
As a consequence, the variability of ab-
sorbed dosage can be large if the product
is not robustly formulated.
Even for materials where bioavailabil-
ity can be readily enabled, the dosage re-
quired in the product can be incredibly
low, often only a few micrograms or less,
Enabling Technologies McNaughton adds. “This situation pres-
ents the secondary challenge of achieving
homogeneity within the product, where
Advance Poorly Soluble an individual particle of the HPAPI may
be a large portion of, or sometimes even

Highly Potent APIs bigger than, the specified dosage,” he says.

The particle size of APIs can strongly
influence the rate of dissolution. With
Cynthia A. Challener this approach, according to Jessica
Mueller-Albers, strategic marketing di-
rector for oral drug delivery solutions
at Evonik, the concentration gradient
Excipients and new processing between the gut and blood vessels will
be increased to facilitate drug transport
techniques can make a real difference and consequently absorption. However,
in the development of highly potent therapies. micronized particles can be associated
with increased health risks.
“The high potency of these molecules

N
ew molecular entities have con- morphologies, poorly soluble HPAPIs can create potential exposure concerns
tinued to increase in potency over can pose additional challenges with re- for workers, even at extremely small
the past decade as pharmaceutical spect to formulation development and amounts. There is a need for specialized
and biotechnology companies seek to manufacturing. Several enabling tech- processes and expertise in the handling

FOR PERSONAL, NON-COMMERCIAL USE

improve treatment options for oncol-
ogy and other chronic and rare disease
nologies are helping drug makers and
their outsourcing partners overcome
and containment of the drug substance,
as well as intermediates resulting from
areas. Approximately 70–80% of drugs these hurdles. particle engineering and the manufac-
in the pharmaceutical pipeline exhibit turing of the finished drug product,”
low solubility and fall into the Biophar- Multiple challenges she notes.
maceutics Classification System (BCS) Any handling of HPAPIs requires care, In fact, challenges in containment
Class II or IV, according to a 2015 Mar- appropriate equipment, and good can limit the technology that can be
ket Study by Kline & Co., with the ma- practice to ensure the operator is kept deployed for solubility enhancement, ac-
jority of these compounds being Class safe at all times, according to Alyn cording to Adam Kujath, global senior
II (poor solubility, high permeability) (1). McNaughton, technical director with director of manufacturing science and
Lonza Pharma Biotech & Nutrition Lonza Pharma Biotech & Nutrition. technology at Alcami. “Typical API ap-
reported to Pharmaceutical Technology “Biopharma companies and manufac- proaches for solid dosage forms to im-
that 20% of the current drug develop- turers must be dedicated to ensuring prove solubility like micronization and
ment pipeline is highly potent and/or that operators are able to do their work spray drying are more difficult to outfit
requires special handling and also has safely and without concern for contami- with appropriate containment systems.
solubility or permeability challenges. nation. With the technical challenges of For instance, milling of solids, while not
SHAWN HEMPEL- STOCK.ADOBE.COM

While solubility and bioavailability bioavailability enhancement, additional impossible to do in appropriate contain-
challenges are not unique to highly po- time and dedicated experimental areas ment, poses a challenge since it tends to
tent APIs (HPAPIs) and in the small- can be needed, which can make it chal- create dust in the breathing airspace for
molecule world are highly dependent lenging to meet development timelines,” any worker. For parenteral formulations,
upon their particular moieties and he observes. lyophilization presents a similar chal-
As one example, complex molecules lenge,” he says.
Cynthia A. Challener is a contributing designed to provide targeted activity, The toxicity of highly potent com-
editor to Pharmaceutical Technology. while minimizing side effects, also often pounds also drives low allowable carry-
20 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
overs in the manufacturing equipment at change over. “Low sol- plans, systems, and training are established so that in a
ubility means cleaning reactors is inherently more challenging, worst-case scenario, such as an accidental release, there is
and analytically may provide poor surface recoveries or impact no risk of contaminating the environment and a mechanism
the achievable cleaning method sensitivity. Furthermore, if they is in place to clean the area back to a safe standard without
happen to be organometallic compounds, you have to worry any risk to the operators.
about not only the active compound, but related organometallic
and inorganic metallic species (such as mercury, arsenic, and Excipient options
platinum) as typical byproducts,” Kujath explains. Excipients that are helpful in any low solubility drug are gen-
For contract drug-product manufacturers, the first hurdles erally applicable to an HPAPI with low solubility. Solubiliz-
can occur upon receipt of the HPAPI. Packaging systems can ers and disintegrants are two examples, according to Kujath.
vary widely, and it is rare for the manufacturer of an HPAPI and Excipient selection should be based on a combination of the
the product manufacturer to use a common handling system, chemical and physical properties of the HPAPI and the target
according to McNaughton. A suitable mechanism needs to be product profile, according to McNaughton. “Meeting a target
available for accessing the HPAPI in a safe and hygienic fashion. product profile for a poorly soluble API requires both the
correct technology selection and the appropriate science-led
Effective containment formulation development,” he comments.
An effective containment strategy should include clear, stan- While there are no specific excipients that are suited to
dardized processes for equipment startup, as well as defined highly potent materials, there are certain aspects of some
cleaning procedures and robust decontamination procedures, technologies that offer advantages if they are also the cor-
according to Mueller-Albers. “It is integral to have operators rect technology for the product, McNaughton adds. “Under
who are well-trained in the operation of relevant equipment and certain permeability-limited situations or biological obstacles,
procedures for the types of substances being handled,” she adds. there are specific lipidic excipients that can provide some per-
Any handling, introduction, and transfer of powder between meability enhancement, others that inhibit efflux, and others
processing steps must be conducted in a closed or isolated sys- that could avoid first pass metabolism through utilization of
tem, which requires more complex and specialized equipment, the lymphatic system,” he says.
according to McNaughton. “Highly diligent processes are re-
quired to prevent operators and the surrounding environment
from being exposed to dangerous airborne powders,” Mueller-
Albers adds. She notes that in addition to closed systems for
milling, containment systems for spray drying have also im-
proved considerably over the past decade, which has created

FOR PERSONAL, NON-COMMERCIAL USE

opportunities for the spraying of HPAPIs to form amorphous
solid dispersions.
For some technologies, equipment may be specific to the
individual process and require specialized handling protocols.
“HPAPI product manufacturing is most straightforward for pro-
cesses that have minimal steps, can be serially conducted, and
do not require the material to be transferred to a completely
different area,” adds McNaughton. “The resulting process com-
monly needs to be qualified to ensure the containment is suf-
ficient for the product being manufactured so that any resulting
operator contamination is significantly below the level at which
the HPAPI could have a therapeutic effect,” he continues.
Cleaning of processes involving HPAPIs must also be con-
ducted in a closed system and is often the time where there is
the greatest risk of exposure for the operator, according to Mc-
Naughton. A key challenge for HPAPIs is the fact that cleaning
must be conducted to a level at which there is no risk of con-
tamination of subsequent products—a level at which residual
HPAPIs are often difficult to detect. When detection cannot
be achieved, dedicated equipment or even facilities are often
required for a single product to ensure no cross-contamination
with other products is possible.
Even though risks are believed to be controlled or re-
moved, McNaughton stresses that it is important to ensure
Pharmaceutical Technology JUNE 2019 21
API Synthesis & Manufacturing
The use of polymer-based excipients
is widely appreciated in the formulation OTC manufacturer issued FDA warning letter and import alert
of poorly soluble HPAPIs, according to
Repeat violations of good manufacturing prac- According to the letter, the company relied
Mueller-Albers. They play a key role in
tices at its Concord, Ontario, Canada facility has on component suppliers’ certificates of analy-
the formation of solid solutions, stabiliz-
resulted in an import alert issued by FDA on March sis instead of testing components for their
ing the amorphous HPAPI in the solid
25, 2019 and a warning letter, dated May 7, 2019, identity, purity, strength, and quality, violat-
state to prevent recrystallization, and also
for Petra Hygienic Systems International, LLC. ing requirements in 21 Code of Federal Regula-
helping to maintain HPAPI supersatura-
The violations included a failure to test product tions 211.84(d)(2).
tion in physiological media, she explains.
for API identity and strength, failure to validate FDA stated in the letter that similar CGMP vio-
Polymeric excipients are also used in for-
outsourced materials, and a lack of written clean- lations were found in previous inspections con-
mulations prepared via granulation using
ing procedures. During a Dec. 17–21, 2018 inspec- ducted in 2012 and 2014.
high-shear mixing or fluid-bed spraying,
tion, FDA found the company had released over- Reference
which can under certain conditions be
the-counter drug products without conducting 1. FDA, Petra Hygienic Systems Int Ltd, Warn-
applicable for poorly soluble HPAPIs. ing Letter, May 7, 2019.
quality testing on finished products as required
by National Formulary monographs or using the
Enabling technologies —The editors of Pharmaceutical Technology
required assay release specifications.
The first HPAPIs were often formu-
lated as liquids and then filled into cap-
sules to reduce safety risks such as dust where these can be fully solubilized be- gies to remove the vulnerable operator
formation. Liquids, however, present cause the potential for poor homogene- from harm include more hygienic valves,
challenges when solubility is an issue, ity is eliminated and accurate dosing can in-line testing to minimize operator in-
according to Kujath. “While microni- be provided, even for the lowest possible teraction with potent molecules, and
zation and spray drying of the HPAPI dose. “Achieving such formulations increased automation that completely
can be helpful for oral solid formula- may be impossible in the solid state, so removes the operator from the vicinity
tions, these techniques to drive initial a lipid/liquid approach can be enabling of these process.
dissolution for liquid formulations can for the molecule to be advanced,” Mc- However, it is important, according
present stability challenges, such as Naughton states. to Kujath, to remember that the issue of
crystallization of an initially dissolved Kujath notes, though, that while low solubility is not unique to HPAPIs
amorphous HPAPI from the vehicle or lipid-based solubilizers and the for- and can be vastly improved in the active
ripening in a micronized dispersion,” he mation of nanoemulsions can be an molecule design process. For instance, he
explains. Thermocycling during termi- effective way to deliver an HPAPI of points to technologies such as antibody-

FOR PERSONAL, NON-COMMERCIAL USE

nal sterilization can also cause ripening
or recrystallization or break complexes
low solubility, these techniques should
generally be combined with the use of a
drug conjugates, which are useful for tar-
geted delivery of small-molecule HPAPIs,
formed by solubilizers such as (2-hy- low-energy means of sterilization. but also offer a means to chemically mod-
droxypropyl) beta-cyclodextrin. ify a pharmacologically active compound
If the API is not “greasy” (logP < 3), lip-
As the number of HPAPIs in devel- ids are unlikely to provide the same im- so it can be more effectively delivered if
opment has increased, however, manu- provements that amorphous dispersions poorly soluble.
facturers have aggressively examined can, according to McNaughton. In addi- “In the small-molecule world, time
new processing techniques suitable for tion, processing to achieve particle-size spent during molecular selection for
oral solid-dosage forms, according to reduction can be simpler than developing not only potency but solubility and
Mueller-Albers. Particle-size reduction, an amorphous or lipid formulation. bioavailability should be a focus in
or particle-size design, amorphous dis- good drug design. That would reduce
persions, and lipid-based formulations Ongoing developments the need for exotic formulations to
are all suitable techniques for improving “Every day the industry is improving con- compensate. Understanding the ac-
the bioavailability for solubility-limited tainment solutions, making it easier to tive sites of drugs and what can be
HPAPI, according to McNaughton leverage HPAPI handling technologies potentially modified allows for better
“Particle size reduction is likely to that previously may have been less ac- structural designs or the creation of
lead to an increase in the rate of solu- cessible,” says Kujath. He also notes that pro-drug analogs to increase solubil-
bility for an API and may provide some more and more focus has been placed ity and bioavailability,” he concludes.
supersaturation effects, but is unlikely on not just patient safety, but on worker
to result in the same level of potential safety. There are always new and im- Reference
increase that can be achieved by amor- proved excipients being developed, new 1. Kline & Co., “Solubility Enhancement
phous dispersions or lipid-based for- approaches, and better understanding in Pharmaceutical Oral Solid Dosage
mulations,” he says. Lipids also offer a of how to use them, agrees McNaugh- Forms: Global Market Analysis and Op-
further advantage for low-dose HPAPIs ton. He adds that improved technolo- portunities,” Report, March 2015. PT

22 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m

 Overcoming Challenges
in Ophthalmic Drug
Delivery Including
Bioavailability and Sterility
LIVE WEBCAST: Wednesday, June 19, 2019 at 11am EDT | 8am PDT | 4pm BST | 5pm CEST

Register for this free webcast at www.pharmtech.com/pt_p/ophthalmic

EVENT OVERVIEW:
Delivery of therapeutics to the human eye is one of the most Presenters
interesting — but challenging — endeavors a formulator can take on. Dr. Barbara Morgan
The anatomy and chemical composition of the eye make it highly Global Pharmaceutical
resistant to pharmaceutical penetration. Successfully circumventing Business Director
Lubrizol LifeSciences
these protective barriers requires intimate knowledge of ocular delivery General Manager
as well as specialized development and manufacturing expertise. This Particle Sciences
webcast will explore solutions to some of today’s most challenging
issues in ophthalmic drug delivery including selection of dosage form, Dr. Robert Lee
options for increasing bioavailability, improving drug stability, properly President
Particle Sciences
handling highly potent APIs, overcoming patient compliance issues,
and meeting the sterility critical quality attribute.
Moderator
Rita Peters
Key Learning Objectives
Editorial Director
■ Review ocular drug delivery, including dosage forms, physiological Pharmaceutical
challenges, and trends Technology
■
FOR PERSONAL, NON-COMMERCIAL USE
Uncover approaches to increase bioavailability of both topical formulations
and/or poorly water-soluble APIs, as well as methods to improve the
stability of injectable drug products
■ Discover how formulators are mitigating patient compliance issues with Sponsored by
controlled release formulations, such as implants, long-acting injectables,
and bioadhesive formulations
■ Consider the various approaches to meet one of the key ophthalmic drug
product critical quality attributes: sterility
■ Understand the special handling requirements across a variety of ophthalmic
drug products, particularly biologics and highly potent compounds such as
steroids

Who Should Attend

■ Formulators, researchers, scientists, biotechnology experts, innovators,
drug/device engineers, and product development managers from: Presented by
• Branded and generic pharmaceutical companies
• Start-ups
• Medical combination-product companies
• Academia

For questions contact Kristen Moore at [email protected]

Formulation
potential approaches to find a strat-
egy to provide the effective delivery of
poorly soluble drugs.”
Amorphous solid dispersions. Used to

Looking overcome limited aqueous solubility and

enhance oral adsorption, amorphous
solid dispersions work by delivering the

Beyond the drug in the amorphous form. “With the

API in a non-crystalline state, less energy
is required for dissolution and hence ab-
Solubility sorption may be enhanced,” Lee says.
However, the potential for amorphous

Horizon formulations to revert to the more stable

crystalline form in storage is a major
limitation of the technique. If the solid-
state reverts to the crystalline form, the
Felicity Thomas
physical characteristics of the API are
affected, which can adversely impact the
solubility and dissolution rates.
“Knowledge of the solid-state charac-
teristics of the API is required for this
approach as amorphous solids may be
metastable and revert to a more stable
crystalline form,” confirms Lee. “Some-
times this is not observed until well into
a stability program, so solid-state char-
acteristics should be assessed in stabil-
ity protocols. Proper processing and the
Exploration of various formulation right selection of excipients are critical
for a successful amorphous formulation.”
techniques is vital to provide effective Complex formation. In this technique,

FORof PERSONAL,
delivery poorly soluble drugs.NON-COMMERCIAL USE the drug and the matrix interact in an
aqueous environment, forming a com-
plex. The formed complexes augment

P
oor solubility is becoming increas- improve solubility or dissolution rates dissolution and bioavailability of poorly
ingly prevalent within bio/pharma of these complex molecules is vital.” soluble APIs through a low association
drug development and is a trend constant, and can also enhance the sta-
that is anticipated to continue to grow A range of techniques bility of the drug product. In inclusion
as a result of the industry drive to- There are several techniques available complexes, for example, stability is im-
ward development of more molecularly to help enhance solubility of drugs proved as the API is encapsulated (fully
complex chemical entities. Yet, poorly or to improve its dissolution rate so or partially) within a hydrophobic cav-
aqueous soluble compounds are not that a finished product with sufficient ity of the host molecule.
readily bioavailable for humans, and bioavailability can be developed. Ap- “Cyclodextrins have mainly been
as such, these theoretically effective proaches such as amorphous solid used as complexing agents to increase
therapeutic molecules are severely lim- dispersions, complex formation, and the aqueous solubility of poorly soluble
ited in value. nano-suspensions are among some actives,” Lee says. “Different cyclodex-
“Without exploring alternative for- of the common methods employed trin derivatives are available, and suc-
mulation techniques, actives that are within the industry, Lee adds. cessful development relies on the abil-
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highly effective in theory or during “It is important in development to as- ity to select the best analogue at the
in-vitro testing may never progress sess a range of techniques to address right concentration.”
through the development pipeline, the molecule-specific challenges that Yet, Lee goes on to explain that as
and patients may never be able to ben- become apparent during pre-formula- cyclodextrin formulations are in-
efit from them,” states Robert Lee, PhD, tion,” he continues. “Armed with the tended to be solutions, the complexes
president of Particle Sciences. “There- proper knowledge and tools, formula- are governed by thermodynamics and
fore, exploration of effective methods to tion scientists can narrow down the have different equilibrium binding
24 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
 Enhancing bioavailability with hot-melt extrusion

Hot-melt extrusion (HME) is a well-known process within industry, being used a continuous unit operation, allowing fast development and scalability. HME
since the 1930s, and more recently has found prominence in the pharma in- is well placed to serve as an effective anchor for an integrated continuous
dustry within the application of enhancing the bioavailability of APIs. As the manufacturing line, whether that means sequencing a continuous blender to
industry is witnessing a surge in the number of poorly soluble drug molecules the extruder or sizing and compressing unit operations downstream.
entering the development pipeline, techniques to improve solubility will in- A well-developed ASD formulation and HME process is robust and well
evitably continue to experience growth. controlled, enabling the production of consistent product quality both intra- and
To learn more about HME, its advantages, limitations, and recent advances, inter-batch. Furthermore, HME provides an option to formulate drug products
Pharmaceutical Technology spoke with Michael Dennis, director of technical for molecules which have zero or limited solubility in organic solvents.
operations, science and technology, and Bill Huang, senior principal research PharmTech: Are there specific limitations of HME that should be considered?
scientist, formulation sciences, both from AbbVie. Dennis and Huang (AbbVie): Since HME depends on melting the polymer
PharmTech: Can you give a brief overview of HME and how it can aid in and drug, thermally sensitive API molecules and potentially some polymers
solubility/bioavailability enhancement? may not be suitable. Additionally, as a result of the inherent characteristics of
Dennis and Huang (AbbVie): Historically, HME was used to convert raw materials BCS Class II and IV API molecules, it is challenging to attain high drug loading
into a homogenous solid with a particular shape. In pharmaceuticals, it also enables in many cases. Further, the choice of pharmaceutical grade polymers and
dissolution of APIs into a polymer to form a matrix known as an amorphous solid surfactants that are suitable for HME is still very limited.
dispersion (ASDs). ASDs achieve higher apparent solubility and faster dissolution for PharmTech: Could you highlight the most recent advances in HME?
enhanced absorption of poorly soluble compounds (BCS Class II and IV). Dennis and Huang (AbbVie): Absolutely, there are numerous efforts
In an ASD, solute molecules are dispersed molecularly randomly within the being made by industry to advance HME. For example, the understanding of
amorphous carrier. This allows for a drastic significant increase in the apparent fundamental aspects of formulation and drug release has been dramatically
solubility and dissolution rate achieving high bioavailability and better human improved in recent years, which is aiding HME product and process design and
pharmacokinetic/pharmacodynamic performance. A rationally formulated ASD development. We have also seen industry embrace the rigorous application of
generates drug-rich amorphous nanodroplets that maximize the surface area physicochemical characterization tools that are helping in the understanding
of the compound for improved absorption when contacting the dissolution of the impact of physical and thermal properties of materials (constituent
medium as the carrier dissolves. components as well as drug-polymer and drug-surfactant interactions) on HME
While this technology is gaining significant traction in the pharmaceutical processing and product characteristics. We are also seeing a surge in the use of
industry, especially in the oncology therapeutic area, it is key for anyone one-dimensional and three-dimensional computational models to optimize HME
developing in this area to have a solid understanding of HME or to partner processes, which is a result of computational power increases and more efficient
with someone with a strong and long tenure in understanding its nuances to algorithms for discrete element models and computational fluid dynamics.

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ensure timely entry into the market. Through this improved understanding, it is becoming easier to develop robust
PharmTech: What are the advantages afforded by HME over other available formulations and processes with reduced development time and costs.
technologies/solutions aimed at enhancing solubility/bioavilability? Various custom in-house modeling tools have been developed by companies,
Dennis and Huang (AbbVie): A major advantage is that it does not use enabling scientists to select the appropriate polymers, surfactants, and drug
organic solvents. This significantly reduces or minimizes both environmental concentration, which is supporting faster and more efficient drug development.
and safety concerns. In spray drying, an alternative method for manufacturing Additionally, in recent years, there have been significant research efforts made
ASDs, for instance, organic solvents are required to dissolve the polymer and by excipient suppliers to advance HME through the development of new polymer
drug and then the solvents are removed during spray drying and a subsequent systems (e.g., hypromellose acetate succinate and graft polymers).
product drying step. In addition to HME processes being applied to traditional solid oral drug products,
Other benefits of HME when comparing to other techniques, such as they are also now being used in the formulation of biodegradable implantable
spray-drying, is that it offers shorter cycle times, a smaller footprint, and products, such as poly lactic acid- and poly glycolic acid-based implants.
lower capital costs, which all add to its efficiency. Moreover, it is inherently —The editors of Pharmaceutical Technology

constants. “Binding is an equilibrium the encapsulation process to obtain a proving the rate of dissolution, which
phenomena, so large molar excesses true solution.” is inversely proportional to the diam-
are sometimes required for adequate Nano-suspensions. Useful for oral and eter of the drug particle. “Additionally,
complexation,” he notes. “In some inhaled drug products and especially nanomilling improves the homogeneity
cases, it may take 8 g of a cyclodextrin beneficial for parenterals, nano-suspen- of a drug product and therefore content
to encapsulate 300 mg of API. This is sions involve the dispersion of nanome- and dose uniformity,” Lee says.
a relatively high dose of cyclodextrin ter-sized drug particles in an aqueous Nanoparticulate suspensions, there-
and may be associated with real or per- vehicle. In top-down methods, the API fore, behave in a similar fashion to a mo-
ceived toxicity. Also, we have encoun- undergoes nanomilling to increase the lecular solution, and from a manufactur-
tered cases where we had to optimize exposed surface area, ultimately im- ing standpoint, Lee states that the process
Pharmaceutical Technology JUNE 2019 25
Formulation
overall is efficient, reproducible, and be dosed by virtually all routes of ad- such as emulsions (hydrophobic core)
highly scalable. “However, identifying ministration,” he says. or liposomes (hydrophilic core) offer
the proper formulation composition and The improvement in bioavailability a micro environment that is either hy-
process are key, and a typical challenge is that is gained through nanomilling drophobic or hydrophilic but not both.
identifying a formulation that maintains can be attributed to the fact that during The LyoCell micro environment offers
its stability over time,” he adds. “For a for- the milling process, drug particles are both, and is therefore, better suited for
mulation to be developed effectively, it reduced in size to below 1000 nm, typi- typical drug-like molecules that are
requires highly experienced individuals cally as low as 100–200 nm, Lee explains. often amphiphilic (i.e., containing
who truly understand the process.” “The conversion to nanocrystals thereby both a non-polar hydrophobic region
So, despite the seemingly simple increases the surface area-to-volume and a polar hydrophilic region).”
concept of nanoparticulate suspen- ratio of the API, which allows for greater The technology is intended for a
sions, development may not be as interaction with water, which in turn range of applications, suitable for a
straightforward, with success being increases the API dissolution rate,” he wide variety of dosage forms, and
dependent upon the right combina- adds. “Essentially, nanomilling gener- employs generally recognized as safe
tion of an experienced team of scien- ates smaller particles of API, which can (GRAS) ingredients.
tists and data interpretation to avoid dissolve more readily. This creates a high
formulation pitfalls. “Nanoparticulate concentration gradient that facilitates Conclusion
suspensions tend to become unstable the transfer of the API across biological Industry has witnessed a surge in the
and agglomerate over time, due to high barriers including membranes (i.e., GI number of poorly soluble molecules
surface energy of the particles, and tract and blood brain barrier).” being targeted for development to treat
can also exhibit Ostwald Ripening, Furthermore, nanomilling can be ap- specific diseases over the past decade.
whereby small particles preferentially plied to nearly all insoluble APIs, Lee As a result of this trend, solutions to
dissolve and then re-crystallize onto confirms, and the approach can be eval- overcome solubility and bioavailabil-
the larger particles,” Lee says. uated easily with only minimal quan- ity challenges presented by these mol-
Therefore, he explains that a key fac- tities of API, which adds to its appeal ecules are ever more vital to ensure
tor in generating a viable formulation is during initial proof-of-concept study promising molecules can be presented
the optimal selection of a stabilizer. Not stages of development. “Nanomilling is and delivered to market for safe and
only must this selection process take also a particularly efficient, reproduc- effective use by patients.
into consideration the physicochemical ible process that is very scalable. Once “Molecules will continue to require
and pre-formulation data on the API, initial feasibility has been assessed and a ever more complex and advanced drug
but it must also factor in the primary nanomilling process is optimized, there delivery technologies that address in-

FOR PERSONAL, NON-COMMERCIAL USE

properties of the stabilizers themselves.
“In general, there is no ‘one-size-
is minimal variation in particle size
from batch to batch,” he emphasizes.
soluble compounds,” notes Lee. “Not the
‘one-size-fits-all’ or ‘put it in a tablet’ ap-
fits-all’ approach to the selection of “This formulation approach is easy to proach that may have worked in the past.”
nanoparticulate suspension stabiliz- scale to production, as commercial There are a variety of approaches
ers, so often an iterative process of op- nanomilling equipment typically uses available that can be employed by for-
timization of stabilizer selection and a recirculation process that allows batch mulators to tackle the issue of solubility
concentrations is necessary to achieve sizes to increase without changing the and increase bioavailability of poorly
the final desired formulation,” Lee em- process variables.” soluble or insoluble APIs. However, ex-
phasizes. “For example, in some cases, perience and expertise on how to best
two nanoparticulate suspensions may Growing interest in apply these techniques is required to
have essentially identical particle size combination approach give formulations the best chance of
distributions and physical stability but As an example of industry trends, Lee success, Lee stresses.
vastly differ in oral bioavailability.” reveals that Particle Sciences has been “Challenges in overcoming limited
witnessing a growing interest in its in- solubility won’t go away any time
The appeal of nanomilling licensed technology, LyoCell, which soon. But by using a rational approach
Out of all the approaches to formu- combines a lipid-based approach with to drug development, we can continue
lating insoluble APIs, Lee specifies nanoparticles. “The technology uses to overcome them and expand our
that nanomilling holds great appeal, a reverse cubic-phase matrix, which knowledge base,” Lee summarizes.
as it is a technique that is useful for assures the hydrophobic and hydro- “Central to this knowledge base is being
yielding a product with improved philic domains in these nanoparticles data driven and utilizing a range of
delivery and bioavailability. “Used in are never more than a few nanometers techniques during formulation devel-
FDA-approved drug products since apart, potentially leading to unique opment alongside having the analyti-
the year 2000, the nanocrystals that solubilization properties,” he explains. cal and production support to take the
result from a nanomilling process can “Alternative lipid-based approaches drug products forward.” PT
26 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
Inhalation Drug Manufacturing
drug is automatically delivered when you
are inhaling and before your lungs are
full. In addition, the display can visually
prompt patients on how to use it correctly.
This inhaler has been designed to be reus-
able. The main electronics component is
reusable with up to 12 monthly refills of
the medicine.
PharmTech: What are some of the benefits
of connecting inhalers to a smart device?
Griffiths (3M): It stands to reason that
you can get better patient engagement
through ease of use, which can lead to
improved compliance. My interpreta-
tion of compliance is twofold. The first
element is adherence. Is a patient taking
his/her medicine at the right time, in the
right amount, as prescribed? On a daily
basis? Morning and evening? The correct
Considering Connected number of puffs each time, as necessary?
Are they doing that routinely?

Inhalation Drug Delivery The second element is technique. With

inhalation therapy, the delivery of the
medicine can be greatly affected by how a
patient uses a device. We see many deliv-
Jennifer Markarian
ery issues with press-and-breathe inhalers,
soft mist inhalers, and dry powder inhalers.
With some dry powder inhalers, a patient
A connected MDI may encourage needs to use a lot of inspiratory force to de-
liver the drug, which is difficult for some
compliance and aid proper technique. patients with respiratory diseases to attain.

FOR PERSONAL,
regulatory NON-COMMERCIAL USE Technology can help in both areas. An

C
considerations for connected
an “smart” drug-delivery devices im- inhaler that is connected with a smart
prove patient compliance? Innovators combination drug-device products. device can send reminders to a patient to
at 3M think so. Improving adherence help with adherence, for example. It also
and reducing use errors in noncompli- Patient-centric design has the potential to help improve tech-
ant patients have been associated with PharmTech: Can you brief ly describe nique by providing feedback to a patient.
improved health outcomes, and smart how the 3M Intelligent Control Inhaler The 3M Intelligent Control Inhaler was
inhalers have the potential to help accom- functions? designed with the potential to do this. We
plish this objective, says Stewart Griffiths, Griffiths (3M): Most pressurized metered wanted to have the ability to tell patients
a product commercialization manager for dose inhalers (pMDIs) on the market re- when they’re not breathing in for long
3M Drug Delivery Systems Division. “As a quire you to coordinate your inspiratory enough or when they’ve not shaken the
society, we’re growing more accustomed flow when you press down on the canister medicine if it needs to be shaken. Technol-
to getting the information we want faster to release the medicine. If you breathe in ogy gives us the ability to coach and guide
than ever before and in a way that is tai- and your lungs are nearly full by the time patients in the real world, without having
lored to our individual preferences,” he you press, you’ve pressed too late. Con- to be in a doctor’s office.
notes. “Everything is personalized and versely, you may press too early in the PharmTech: How do you incorporate
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on demand. We are starting to see this inspiratory cycle. When you mistime it, human factors engineering into a de-
becoming true with regard to how drugs less medicine than intended is absorbed. vice design?
are delivered to patients and the instant The 3M Intelligent Control Inhaler was Griffiths (3M): From my perspective, it
feedback they expect.” Pharmaceutical designed such that it could utilize the fa- is important to get the device into the
Technology spoke with Griffiths about the miliar MDI dosage form and add value by hands of patients as early as possible—for
company’s 3M Intelligent Control Inhaler, aiding patient coordination. It uses breath example, through formative human fac-
which is currently in development, and actuation to help correct the coordination tors studies in the early prototype stage.
about some of the manufacturing and problem, so you just breathe in and the These studies allow the scientist in the lab
Pharmaceutical Technology JUNE 2019 27
Inhalation Drug Manufacturing
to use input from real patients to design need to instill trust in patients from the devices requires a shift from purely plas-
new inhalers that are easy to use, fit com- very beginning. To do that, we need to tic components to the incorporation of
fortably in hand, and are easy to actuate, make sure patients understand how and electronic components. This not only re-
for example. Only when you put it into the why we’re using their data, and we need quires updates to the manufacturing lines
hands of patients will you discover that to clearly demonstrate how they will ben- themselves, but to the testing facilities. If
it may be fundamentally flawed. Those efit from the use of their data. Today, it historically you’ve worked only with plas-
formative human factors studies act as is critically important to determine the tic materials, tests are purely physical in
inputs that can inform the design of the data strategy before going into design nature. Electronics module testing is very
device. When patients can easily operate and development. 3M has addressed this different. For instance, if your connected
a device, it means the patient receives the by making security part of the up-front inhaler utilizes Bluetooth technology,
correct dose and is more likely to comply development process. electromagnetic compatibility testing is
with the therapy. Finally, regulations around drugs and required to prevent the device from in-
One of the key outputs of a human fac- devices are now becoming intertwined terfering with other connected devices.
tors program is the instructions for how to with electronics and software. 3M’s goal Regulatory standards also change, once a
use the device. The findings will drive what is to be ahead of the curve and follow the device is categorized as connected.
goes into those instructions. They will also regulations as they evolve. The speed of Finally, with technology constantly
inform how the packaging is designed, to electronics and software evolution is changing, the use of electronics allows
ensure that it is easy for patients to open. at a much faster pace than traditional for rapid improvements and the ability to
pharmaceuticals by nature. The industry address real patient issues. For instance,
Regulatory considerations needs to evolve to incorporate electronics improved battery technology can allow
PharmTech: What are the regulatory and but continue in a safe way. a device to be used for a longer period
data security concerns with connected de- PharmTech: What are some of the man- of time. At the same time, it is impor-
vices and how are they being addressed? ufacturing challenges for incorporating tant to keep in mind that the pace of the
Griffiths (3M): Protecting patient privacy electronics into inhalers? Are there special pharmaceutical industry is very different
must be a top priority. There are tremen- regulatory/quality testing considerations than the pace of the technology industry.
dous opportunities ahead for collecting, for connected devices? This can create major challenges on ev-
sharing, and analyzing data generated Griffiths (3M): From a manufacturing erything from the design to the manu-
by digital delivery devices; however, we point of view, the arrival of connected facture of a device. PT

Hovione Technology Develops Blister-Based Inhaler

FOR PERSONAL, NON-COMMERCIAL

In addition to being simple to manufacture, devices need to beUSE
Hovione Technology, a Hovione Ventures company, announced in an April simple for patients
to use correctly. “Inhalers need to work in the hands of the patient. No matter how
15, 2019 press release that it has secured global rights to develop and com-
mercialize a new, affordable, multi-use blister-based dry powder inhaler (DPI) brilliant our inventions are, at the end of the day they need to bring benefit and value
patented by inventor Dr. Klaus-Dieter Beller, which will be marketed as the to the patients,” says Villax. He explains that human factors engineering is central
Papillon DPI (1). The blister-based inhaler is suitable for both chronic and acute for new DPI developments. This systematic design process can capture preferences
treatments and can accommodate a single- or double-blister configuration. The towards design attributes that improve patient engagement with the device.
patient loads a blister to take the daily dose and reuses the inhaler for a defined Creating a simple DPI is not a simple task. It is a difficult “marriage between
period of time, typically 30 or 60 days. device physics and formulation properties,” says Villax. “An inhaled combina-
The simplicity of the device, which is made from a single part, significantly tion [drug] is a complex product, because you have to consider not just the drug
reduces development cost and risk compared to more complex devices, explain product, not just the device, but also how they interact with each other. For
Hovione Technology’s CEO Peter Villax and João Ventura, director of Technology example: a powder inhaler turns an inspiratory effort into a force that disperses
Development and Licensing. “Because it is manufactured from a single mold, and aerosolizes a powder and entrains the particles into the lung. How effi-
manufacturing and depreciation costs are much lower,” they add. ciently this dispersion and entrainment occur is a key feature of the inhaler, but
Villax and Ventura say that simpler DPI designs, which are less costly to manu- it depends just as much on the particles themselves and on how well they fly.”
facture, fulfill the need for readily accessible and affordable treatments, par- Hovione Technology’s co-promotional agreement with API manufacturer
ticularly in less developed markets. “Innovators have traditionally used device Hovione allows the companies to integrate DPI device development with inha-
complexity to increase development and cost barriers for generic competition. lation API formulation development and manufacturing. According to Hovione
[In addition,] smart and connected devices may have a role in the medium-term Technology, Papillon is available for feasibility studies and integrated develop-
to further improve treatment effectiveness and adherence, especially in devel- ment with formulation by pharmaceutical partners.
oped markets,” notes Ventura. “But inhaler devices do not fundamentally need Reference
to be complex; inhaled drugs can be delivered as effectively from devices made 1. Hovione Technology, “Hovione Technology Announces Papillon DPI,”
of very few parts and assembly steps.” Ventura says that making simpler inhaler Press Release, April 15, 2019.
devices is also a “greener” solution that consumes less resources. —Jennifer Markarian

28 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m

Scale Up
to help advance end-to-end continuous
manufacturing, from API to finished
product.

QbD becomes more dynamic

A number of speakers suggested that
the concept of pharmaceutical quality
by design (QbD) is becoming much
more dynamic than what was outlined
in the first FDA guidance on that topic.
As pharmaceutical manufacturers have
become more comfortable with more
advanced process control, the empha-
sis is moving from the design space to
greater use of feedback control. The

Batch or Continuous? idea, according to Zoltan Nagy, a pro-

fessor at Purdue University’s School
of Engineering, is “to make critical
Ask the Right Questions quality attributes tunable so that the
system can find the conditions at
which it needs to operate in order to
During Scale Up ensure product quality.” Ajaz Hussain,
director of the National Institute for
Pharmaceutical Technology and Edu-
Agnes Shanley cation (NIPTE), spoke of the need for
reproducibility and repeatability, and
to move from “one size fits all” attri-
butes to multivariate personalization.
Continuous manufacturing may offer huge “Twenty-first century quality and cures
demand continual improvement and
opportunities, but it will not be right for confidence, and that will require dy-

FOR
every PERSONAL,
facility or product. NON-COMMERCIAL USE namic feedforward and feedback con-
trol,” he said. For a full report on the
symposium, visit PharmTech.com.

O
n May 6, 2019, at St. John’s Uni- turing requires. “How can we make
versity in New York City, the 11th continuous manufacturing easier for Scale-up considerations
annual Charles Jarowski Sympo- late adopters? In the end, we need to Focusing on scale-up issues was Mi-
sium in Industrial Pharmacy examined promote the quality of medicines, how- chael Rooney, director of process en-
the challenges and opportunities posed ever they are made,” said Dubey. “We gineering at Genesis Engineers, who
by continuous pharmaceutical manu- will also need to be able to produce considered some of the challenges that
facturing. A number of commercial drugs that were approved as continu- existing manufacturing operations
products are already being made con- ously manufactured products so that face when considering the implemen-
tinuously, and more than 20 products they can be made via batch manufac- tation of a continuous manufacturing
that are now awaiting FDA approval turing,” he said, “since the reality is approach to scale up oral solid dosage
use continuous manufacturing, said that not all manufacturers will em- (OSD) forms or replace a batch process
Atul Dubey, director of pharmaceuti- brace continuous manufacturing.” with continuous. As he explained, one
cal continuous manufacturing at the At the program, experts from Merck cannot simply inject continuous man-
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United States Pharmacopeia (USP), and Takeda discussed continuous ufacturing into a batch facility, espe-
who spoke on the program. manufacturing pilot development pro- cially because legacy facilities tend to
A crucial question is what the incen- grams underway at their companies, be single or two stories, and floor-to-
tives will be for generic pharmaceutical university professors summarized re- floor distances do not help vertically
manufacturers, which supply most of search findings, and Bayan Takizawa, integrate continuous. Rooney used two
the prescriptions written in the United cofounder and chief business officer different case studies to illustrate the
States, to invest in the technology and at Continuus Pharmaceuticals high- challenges of justifying the cost to con-
knowhow that continuous manufac- lighted pilots and projects underway vert to continuous. One involved the
Pharmaceutical Technology JUNE 2019 29
Scale Up
expansion of a commercial drug using product cost and the company wound Rooney: Generally, continuous will
a dry granulation process in an estab- up investing more in its batch process be most practical for processes that in-
lished facility, the other, expansion of to avoid undue risk. “Continuous man- volve direct compression or dry gran-
a high volume over-the-counter (OTC) ufacturing may be great for flexibility ulation. With direct compression, one
product that did not involve API. In but it should not be used as a capacity is mixing components with minimal
this case, he said, reducing labor costs solution,” Rooney said. “People tend to manipulating. In dry granulation, ma-
was the primary goal. emphasize the potential for continuous terial is densifed with a roller compac-
tor, milled, blended, and compressed
with a tablet press. Tablet press equip-
“People tend to emphasize the potential for ment has long been based on a con-
tinuous process anyway. In addition,
continuous manufacturing to reduce [costs] the percentage of active shouldn’t be
too low if a continuous approach is to
... but it may require increased investment work well, or at least be easy to imple-
in PAT, process development, data handling ment. In some new oncology drugs, the
API is so potent that drugs may only
and storage, and recall strategies.” contain about 1–5% active ingredient.
Using continuous manufacturing for
— Michael Rooney, Genesis Engineers these products can be very challeng-
ing, even though it is possible, because
of the need to guarantee plus or minus
Conflicting material flows manufacturing to reduce the cost of 10% of label claims.
In both cases, he said, using the con- goods sold (COGS), but it may require In addition, these formulas typically
tinuous manufacturing scenario, the increased investment in PAT, process use a large number of other functional
f lows of people and raw material development, data handling, and stor- components (e.g., pH neutralizers and
conf licted. “What began as a capac- age and recall strategies,” he said. disintegrants). Sometimes up to 14 dif-
ity question ended up as a question of In the end, companies must deter- ferent components may be required, all
return on investment,” he said. For one mine what will be more cost effective: in differing quantities. The best can-
thing, with the branded drug company, reducing operator labor and facility didates for scale up using continuous
it was found that the building, which costs or reducing time to market and manufacturing are products that in-
was only 25 feet high, would need to starting to recoup product revenue volve dry granulation and direct com-

FOR PERSONAL, NON-COMMERCIAL USE

be 60 feet high to accommodate con-
tinuous manufacturing. In addition,
sooner. For most companies, the transi-
tion to continuous manufacturing will
pression, products where API percent-
ages aren’t too low, and where there
the shift from batch manufacturing be driven by product development sci- aren’t too many diverse excipients in
would involve higher operating costs entists and engineers sooner than it will the formulation.
due to highly skilled technicians to at- by the operations group, Rooney said.
tend to the PAT technology. The com- In addition, savings may often be more Making the case to management
pany, which had been trying to justify pronounced in Phase II and Phase III PharmTech: Are there considerations
moving to continuous manufacturing projects, rather than commercial pro- that people may forget when they
on the back of one major product, is duction. In an interview after the con- propose continuous manufacturing
now working on building a continuous ference, Rooney shared some insights projects to corporate managers?
platform. “If you develop a platform for into continuous pharmaceutical scale Rooney: On the manufacturing side,
groups of product types, rather than up with Pharmaceutical Technology. the idea to use continuous often comes
try to replace existing batch capacity from managers who see continuous as
with continuous, it doesn’t have to run Labor or time-to-market? a way to reduce labor and equipment
100%. You can build a platform and a PharmTech: Are there some basic mis- footprint. Continuous will save both,
portfolio over time,” Rooney said. understandings in the industry today but there are other factors to consider.
In the second case, with the OTC about continuous manufacturing and In batch OSD plants, when you move
product, second-level infrastructure how easy it is to scale up? material around you promote segrega-
costs hurt financials and there was Rooney: I’m a real proponent of con- tion or unblending. Continuous mini-
no subject matter expert on site to de- tinuous manufacturing, but it’s not mizes this movement, so managers
velop the process analytical technology perfect for everything. may think it will help reduce segrega-
(PAT) required for continuous, Rooney PharmTech: What would make a pro- tion and even reduce the need to wash
said. In this facility’s case, moving to cess an ideal candidate for continuous bins as frequently. But this is only part
continuous had no real impact on manufacturing? of the challenge. Based on data gath-
30 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
ered during continuous manufactur- bulk containers. One of the big advan- Rooney: I expect to see faster integration
ing, facilities can use real-time release, tages of continuous is that it allows a of continuous manufacturing in the
eliminate testing and product quaran- facility to bring raw material contain- OTC market, particularly for supple-
tine and release to distribution. There ers straight into your plant and not ments. These lines run at much higher
is no worry about batch size, because stop to dispense individual batch ma- speeds and labor is a big component of
batches are defined by time, with pro- terials. However, this is the opposite of their cost of goods. Continuous manu-
cess validation documents establishing what people in batch plants have been facturing allows OTC manufacturers
the maximum operating window. The doing for the past 20 years. to reduce operating costs.
challenge comes with using PAT. One In most batch facilities today, the For generic pharmaceuticals, the is-
has to characterize that product that dispensary is the dividing line between sues are different. Branded companies
is going through the process. Current current good manufacturing practices are not all going to share their develop-
PAT technology is capable of generat- (cGMP) and non-cGMP operations. ment databases, monographs, and ap-
ing data in a matter of seconds and ac- Bulk corrugated containers can intro- proaches to PAT, so generics manufac-
cumulating data very quickly, that has duce contaminants into a facility. In turers would have to invest in the same
to be controlled, stored, and potentially general, the flows that are required for development that branded companies
retrieved at a later date. The equipment continuous manufacturing are coun- have to do. I expect to see more con-
cannot run without the PAT working, terintuitive to what people generally tract development and manufacturing
but then how does the PAT system have, and there is a very different space organizations (CDMOs) investing in
know how to work? classification for each. continuous manufacturing. Generic
PAT learns the comparator or mono- pharmaceutical manufacturers would
graphs, which ref lects thousands of More CDMOs working in continuous be more likely to work with these
hours of development. PAT takes a PharmTech: What might convince more CDMOs, to avoid having to invest in
snapshot of what is moving past the generic pharmaceutical manufacturers continuous manufacturing technology
analyzers, and compares the value to to invest in continuous technology? and expertise themselves. PT
that from a monograph. But what if
some peaks have shifted? There can be
different sources of variability, which
require multivariate analysis. This is
not strictly an equipment decision.

Consider facility layout

FOR PERSONAL, NON-COMMERCIAL USE
PharmTech: Do people underestimate
the challenges posed by facility layout?
Rooney: With continuous, one at-
tempts to solve a lot of problems about
particulate separation by coupling
everything (e.g., placing feeders near
blenders, and blenders near mills). An- AVAILABLE: BIOPHARMA OPPORTUNITY
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formulation from batch to continuous
considering the number of raw materi- $LUSRUW%OYG%RXOGHU&2
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that all these feeders must be fed via

Pharmaceutical Technology JUNE 2019 31
 Peer-Reviewed

Defining and Managing

Raw Manufacturing Data
Orlando López

Protecting the integrity of raw data is crucial

D
ata integrity ensures that information stored during phar-
to regulatory compliance and to proving maceutical manufacturing is reliable and trustworthy.
that manufacturing and quality operations Electronic records (e-records) pose special data integrity
are being run and managed properly. challenges. Links between electronic data, raw data (i.e.,
the first capture of information, whether recorded on paper or elec-
tronically [1]), metadata, and records must not be compromised
or broken if the data and their relationships with other data are
to be valid.
Preserving the integrity of the raw electronic data generated by
manufacturing and quality operations is crucial because these data
provide the only evidence that these departments are being run
and managed correctly and in a way that complies with regula-
tions. It is the foundation for continuous process verification (CPV)
and process validation. Technological controls must be in place
to ensure the integrity of these data. This article discusses these
controls and how they should be implemented for identification,
storage, protection, retrieval, retention time, and disposition of

FOR PERSONAL, NON-COMMERCIAL USE current good manufacturing practice (cGMP) records (2).

Data lifecycle
The data lifecycle (Figure 1) helps to map and explain the controls
that are necessary to manage data, raw data, metadata, and records
(3) properly. Data access control is crucial, for example, and any
changes to an e-data point can only be made by someone who
has been authorized to make those changes. Failure to address
even one element of the data life cycle will weaken the overall ef-
fectiveness of controls implemented for the computer system and
for e-data integrity.
During the data capture stage, data are collected and related
actions are performed. Then, during transformation, the data are
scaled and converted, and then built-in checks (summarized in
European Union [EU] Annex 11-11 [4]) are performed to verify
that all the data are correct after the transformation.
AUREMAR - STOCK.ADOBE.COM

Because the data transferred during this stage move between

process equipment and the computer, the interface between the
two should be validated and checked periodically to ensure accu-
racy. The accuracy and reliability of the raw data depend not only
on properly calibrated and maintained instruments and equip-
ment, but also on the integrity of the raw data that have been re-
Submitted: January 4, 2019 corded. When instruments and equipment cannot ensure secure
Accepted: January 24, 2019 data access and administration of electronic data files, collected
32 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
FOR PERSONAL, NON-COMMERCIAL USE
Peer-Reviewed
such raw data become a cGMP record (7). Examples of raw data
Figure 1: Data lifecycle.
in a typical manufacturing environment include:
Commit to collect • Analog readings (e.g., of temperature, pressure, flow rates,
levels, weights, central processing unit [CPU] temperatures,
Work in
progress mixer speeds, or fan speeds)
Capture and transformation • Digital readings (e.g., of valves, limit switches, motors on/off,
and discrete level sensors)
Processable Data

Commit to use • Product information (e.g., IDs for product, batch, material, or
Data
change raw material lot)
management • Quality info (e.g., process and product limits, custom limits)
• Alarm info (e.g., out-of limits or return-to- normal signals).
Active phase
access and use The raw data hold the content of the e-record that will repro-
duce the full cGMP automated activities (8). Properly recorded
and managed raw data are the foundation that is required to
demonstrate the product identity, strength, purity, and safety. The
e-records associated with raw data demonstrate that the manufac-
Commit to archive
turer’s processes meet the requirements of cGMPs, including those
for process sequencing and instructions (9).
Archiving

Inactive phase Accurate management of data during entry or collection, stor-

age, transmission, and processing (10,11) provides controls re-
quired for the processing and retention of loaded data, raw data,
and e-records. The integrity of manufacturing raw data is a basic
prerequisite to CPV, an essential part of FDA’s process validation
requirements. CPV is designed to provide continual assurance that
Discard Purging of records the process remains in a state of control during commercial manu-
Deletion of records facturing. The collection of information about the performance of
the process will allow detection of undesired process variability so
that the process remains in control.

data can be passed directly to a secure environment (typically a Identification of cGMP records
supervisory control and data acquisition [SCADA] system or data Identification to the cGMP records (12) and associated controls

FOR PERSONAL, NON-COMMERCIAL USE

historian) for processing and recordkeeping.
After the data have been transformed and used, they must be
are crucial to the success of any pharmaceutical manufacturing
operation. The characterization of these cGMP records usually
moved to a recordkeeping environment where they can be edited starts with a primary design document such as a process and in-
for as long as necessary as the data are retained. During the active strumentation drawing (P&ID). A process flow diagram (PFD) or
phase (i.e., when data are actively being used), raw data may be some other form of schematic may also be used.
cleansed periodically to correct inconsistent values after they have Table I depicts the critical process parameters for a solid dosage
been used. Periodically, data must be reconciliated. Cleansing or form manufacturing process. Process equipment incorporates
data cleaning is performed to detect and correct corrupt or inac- instrumentation designed to control the process and acquire data
curate records from a record set, table, or database. This activity about each critical process parameter.
must be suitably managed and documented (e.g., by establishing The primary goal for controllers is that they work accurately
an audit trail). The inactive phase starts with records archival, in the intended process. The controllers are dynamically verified
which applies to inactive, superseded, replaced, and withdrawn during the qualification of the automated cell controller. The cell
data. These records must be kept to meet the data retention sched- controllers are typical Level 0 in the ANSI/ISA-95 and essential
ule and traceability requirements. These records usually maintain to ensure proper functioning of the process and product quality.
“read” and “view” attributes. There are exceptions, however, in The input/output (I/O) list refers to the information that comes
which “processability” may be extended for the full life of the re- into and goes out of the manufacturing system.
cords through to discard. In Table I, for example, the air temperature, air volume dew point,
All figures courtesy of the author

and product temperature are the I/Os associated with a fluid bed
Pharmaceutical manufacturing operations dryer (13). Field instruments provide measurements of these values
In these types of operations, data that have been loaded from field from field instruments via terminating wires in the digital system
sensors contain a measurable attribute of a physical entity, process, I/O processing section. After transformation, the data are trans-
or event (5). The loaded data are recorded, becoming raw data, mitted to the SCADA system over the communications link.
which are considered “original” or “source captured” (6). When The first step in documenting the I/O requirements is to com-
multiple raw data are generated to satisfy a cGMP requirement, pile a list of all the applicable points that are referenced on the
34 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
 Table I. Critical process parameters for solid dosage form manufacturing.
Process Critical process parameters

Blending time
Blending
Number of revolutions of the blender
Kneading time
High shear wet granulation Impeller and chopper speed
Binder addition time
Inlet air temperature
Fluidization air volume
Fluid bed drying
Dewpoint
Product temperature
Roll gap
Roll width
Roller compaction
Roll pressure
Screen size
Spray volume
Fluid bed granulation Spray rate
Inlet air temperature
Milling Screen size
Compression force
Compression Compression speed
Dwell time
Spray rate
Coating
Inlet air temperature
Speed of encapsulation
Encapsulation
Tamping pressure

FOR PERSONAL, NON-COMMERCIAL

P&ID. This is necessary so that the specific signal and terminationUSE
teriorate. Copying information without changing it offers a short-
data can be associated with each point or each instrument. Alarms term solution, ensuring that information is stored on newer media
and reporting requirements must also be considered. before the old media deteriorate to the point where the information
can no longer be retrieved.
Storage of records To ensure data integrity during storage, any changes that have
Raw data are original records generated by means of computer been made to an e-record must be recorded, including the previ-
systems and become the contents of an e-record. E-records stor- ous entry, who made the change, and when the change was made
age devices record, store, or retrieve e-records from any medium, (14). To reduce the risk of losing the e-records in storage and to
including the medium itself. This is considered a short retention guarantee that they will be ready for use, data must periodically
environment. Design specifications or similar documents must be backed up. Backup data must be stored separately from the
describe the file structure(s) in which the e-records are to be stored, primary storage location, and at a frequency based on an analysis
as well as the capacity requirements of the storage, and how the of risk to CGMP e-records and the capacity of the storage device.
security scheme is implemented. The file structure and security The efficacy of the backup and restore processes must be veri-
are verified/tested during the qualification. fied as part of the qualification process. In addition, the capacity
After the data are recorded and retained by computer storage level of the storage must be monitored. As in archived e-records,
(e.g., historian/SCADA storage), the physical and logical controls the e-records in storage need to be verified periodically for acces-
to the e-records must be in place. These controls include physi- sibility, readability, and integrity. If changes are implemented to
cal protections, stamped audit trail, data management, archival the computer infrastructure and/or application, then it is required
and retrieval of records. Alarms and the associated actions to the to ensure and test the ability to retrieve e-records.
alarms are managed by the programmable logic controller (PLC). One critical element to consider is legal holds to the e-records,
The associated alarm records are saved in the corresponding re- which may exist when the manufacturing company or contract
pository system at the storage device level. Physical protection is manufacturer is involved in litigation. These records cannot be
important because environmental effects can cause media to de- destroyed, even if the data retention period has expired. The regu-
Pharmaceutical Technology JUNE 2019 35
Peer-Reviewed
Figure 2: Data integrity and e-records in process automation. SCADA is supervisory control and data acquisition; I/O is input/output.

Data Integrity and E-records (ER) in Process Automation

Data collected directly from equipment and control signals between
computers and equipment should be checked by verification circuits/
software to confirm accuracy and reliability.
TGA, Code of GMPs, 2013. ER controls for
those items defined
as E-records
Data integrity controls based upon risk

Instruments I/O card Controller Supervisory Historian /

/ equipment System SCADA

Time stamp Time stamped

applied to alarms Controls
process Data associated
with records
Data are transient Data are transient retained by
computer
storage.

E-records are collected

from instruments /
equipment
In general not E-records

lated entity is under a legal obligation to retain all relevant, and Protection of data and records
FOR PERSONAL, NON-COMMERCIAL USE
a legal holds record system or other mechanism must be imple-
mented to identify e-records that would be affected by a legal hold.
The protection of transient data, raw data, and e-records
cover data in storage, during processing, and while in transit
In optimizing physical location requirements for the e-data, (18–20). The protection of transient data, raw data, and e-
web and database servers should ideally be separated. Database records may be set in two environments: transient data be-
servers should be isolated from a website’s demilitarized zone fore reaching the historian/SCADA and raw data, as shown
(DMZ), based on security standards. A DMZ is a physical or in Figure 2.
logical subnetwork that contains and exposes an organization’s Transient data. At the PLC level, the analog data are ex-
external-facing services to a larger and untrusted network, usu- tracted from the PLC memory, transformed (i.e., digitized,
ally the Internet. The purpose of a DMZ is to add an additional validated, normalized, and scaled) and sent to the SCADA.
layer of security to an organization’s local area network (LAN); The data collected directly from manufacturing equipment
an external network node only has direct access to equipment and control signals between equipment and a data server
in the DMZ, rather than any other part of the network (15). (e.g., SCADA) may be regarded as transient and cannot be
These servers can locate them on a physically separate net- edited by reasonable means or reprocessed by the human
work segment from the web and other Internet-accessible servers user. Similar to the controls associated with e-records in
that support the business. Preferably, one should partition the transit, the data integrity controls for transient data are:
database server off from the web servers by a dedicated firewall. • Qualification of the infrastructure. The outcome of this qualifica-
This firewall should only allow database traffic between the web tion provides documentary evidence that accounts for the
server and database server. The firewall should also deny and correct implementation of integrated hardware and associ-
log all traffic from any other location, or other types of traffic ated devices (21).
from the web server. Regulators, and particularly FDA, expect • Built-in checks for the correct I/Os. These built-in checks are, at
that data written in the storage device be saved at the time they first, validated. During the operational stage, the built-in
are generated (16). As appropriate, it is the expectations of the checks must be periodically verified (as required by FDA
regulatory authorities that the data written in the storage device 21 US Code of Federal Regulations (CFR) Part 211.68(b) and EU
must be saved at the time the data are generated (17). Annex 11-5) (22 and 23).
36 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
 • Accuracy checks. Usually performed at the supervisory sys- for a period at least as long as the records for all batches whose
tem level, accuracy checks are required for critical data that release has been supported on the basis of that validation exercise.
have been entered manually by authorized personnel. These For a medicinal product, the batch documentation must be re-
critical data require input verification to prevent incorrect tained for at least one year after the expiry date of the batches to
data entries. which it relates, or at least five years after the certification referred
After the data are recorded and retained, physical and logical to in Article 51(3) of Directive 2001/83/EC, whichever is the longer
controls to the e-records must be implemented and executed. period. At least two years of data must be retrievable in a timely
These controls include security, access authorization, backups, manner for the purposes of regulatory inspection.
periodic reviews, stamped audit trails, built-in checks (required Applicable FDA regulations, 21 CFR 211.180(a), call for data
by FDA Compliance Policy Guide CPG Section 425.400), and that are part of the drug product production and control records
other relevant data-management controls. The PLC manages to be retained for at least one year after the expiration date of
alarms and associated actions, which are saved at the storage the batch or, in the case of certain over-the-counter (OTC) drug
device level. Controls are required if the e-records and associated products lacking expiration dating because they meet the cri-
raw data must be transferred from the original processing envi- teria for exemption under 21 CFR 211.137, for three years after
ronment. After concluding the migration process, verification distribution of the batch. As the results of the traceability re-
must be performed to ensure that the information in the original quirements, the raw data will be retained as specified in 21 CFR
e-records has not been altered. This verified copy becomes a true 211.180(a).
or certified copy. When computer systems are used instead of written docu-
ments, the manufacturer shall first validate the systems by show-
Retrieval of records ing that the e-records will be appropriately stored during the
Access to e-records should be ensured throughout the retention anticipated period of storage. E-records stored by those systems
period (as required by EU Annex 11-7.1). The access to these re- shall be made readily available in a legible form and provided
cords must be controlled to ensure the integrity of the e-records upon the regulators’ request. The electronically stored e-records
in storage. The controls associated with e-records in storage shall be backed up and protected against loss or damage, and
allow those individuals who depend on the e-records to correctly audit trails shall be maintained.
fulfill their job functions.
During the Active Phase, manufacturing e-records will typi- Disposition of records
cally be held in the environment in which the records were ini- If active records are transferred to another environment, valida-
tially created. In this environment, the e-records are visible to the tion should include checks that data have not been altered in
tools that created them. Any features designed to allow them to value and/or meaning during this migration process, as required
be changed or deleted must ensure audit trails that record the by EU Annex 11-4.8.

FOR PERSONAL, NON-COMMERCIAL USE

reason for change or deletion, as well as other information as
required by the applicable regulation. than
E-records that are placed in retention environments, other
the environments that were used for their original cre-
Periodic (or continuous) reviews must be performed after the ation, should preserve the integrity of the raw data, associ-
initial validation (as required by EU Annex 11-11) of the pro- ated e-record, and protection mechanisms used to prevent
cessing environment. These reviews check stored, backup, and informational loss and/or corruption. Should records require
archived e-records for accessibility, readability, and accuracy. modifications in retention environments, a clear audit trail
They also verify the output of the backup and the accuracy of of change or replacement history, including record removal,
the overall audit trail, verifying the accuracy and reliability of should be maintained.
the e-records transferred (WHO 3.2). In addition, processes for Once e-records have been placed in the retention environ-
reading and managing e-records must ensure their data integ- ments, they should never be directly modified. If technical
rity. The infrastructure between the records in storage and the limitations require the electronic record to be modified in the
processing environment must be a controlled environment and retention environment, the change must have traceability to the
must be qualified and checked for accuracy. same change in the processing environment. The inactive phase
starts with records archival. These records need to be kept to
Data retention time meet retention schedule requirements and traceability. These
The EU cGMPs establish that raw data supporting information records usually maintain read/view attributes. Finally, during
in the marketing authorization (24), such as validation or stability the deletion phase, the e-records are discarded. This is a phase
data, should be retained while the authorization remains in force. of short duration and includes metadata and audit trails.
In some cases, periods up to 30 years’ worth of raw data must be
retained. It may be considered acceptable to retire certain docu- References
mentation when the data have been superseded by a full set of 1. UK Medicines and Healthcare Products Regulatory Agency (MHRA),
new data. In such cases, justification should be documented and GXP Data Integrity Guidance and Definition, assets.publishing.service.
gov.uk (MHR, 2018), assets.publishing.service.gov.uk/government/up-
should take into account the requirements for retention of batch loads/system/uploads/attachment_data/file/687246/MHRA_GxP_data_
documentation. The accompanying raw data should be retained integrity_guide_March_edited_Final.pdf.
Pharmaceutical Technology JUNE 2019 37
Peer-Reviewed
2. ISO, ISO 9001:2000 Quality Management Systems – Requirements, 15. Health Canada, “Good Manufacturing Practices (GMP) Guide-
4.2.4 Control of Records, isorequirements.com, (ISO, 2015), www. lines for Active Pharmaceutical Ingredients,” GUI-0104, C.02.05,
isorequirements.com/iso_9001_4.2.3_control_of_documents.html. Interpretation #15 (Health Canada, December 2013).
3. ISPE/PDA, Technical Report: Good Electronic Records Man- 16. B. Mitchell, “Using a DMZ in Computer Networking,” lifewire.
agement (GERM), Collection of Felated Data Treated as a Unit. com, Jan. 6, 2019, www.lifewire.com/demilitarized-zone-com-
(ISPE/PDA, July 2002). puter-networking-816407.
4. European Union, Annex 11-11, www.ec.europa, (EU, 2011) www. 17. FDA, 21 CFR Part 211.160, accessdata.fda.gov, https://www.access-
ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/ data.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.160
annex11_01-2011_en.pdf. 18. EU, Chapter 4 Section 4.8, ec.europa.eu/health/sites/health/files/
5. MHRA, MHRA CGMP Data Integrity Definitions and Guidance for files/eudralex/vol-4/chapter4_01-2011_en.pdf (EU, 2011).
Industry, March 2015. 19. ICH, ICH Q7 GMP Guide for APIs, Section 6.14, www.ich.org/
6. ISPE/PDA, “Technical Report: Good Electronic Records Manage- fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/
ment (GERM),” July 2002. Q7/Step4/Q7_Guideline.pdf.
7. MHRA, “GxP Data Integrity Guidance and Definitions,” March 2018. 20. NIST SP 800-33, “Underlying Technical Models for Information
8. FDA, Data Integrity and Compliance with cGMP, Q&A - Guidance Technology Security,” December, 2001 (Withdrawn: August 2018).
for Industry (FDA, 2018). 21. FDA, 21 US Code of Federal Regulations (CFR) Part 211.68(b).
9. CFDA, Draft Data Integrity Guidance (September 2017 )https://drive. 22. EU Annex 11-5, ec.europa.eu, https://ec.europa.eu/health/sites/
google.com/open?id=0B0GT88vUt4U4ZTBWRkdQWU0xOG8 health/files/files/eudralex/vol-4/annex11_01-2011_en.pdf
(CDFA, 2017). 23. O. López, Computer Infrastructure Qualification for FDA Regu-
10. O. López, Preface, Data Integrity in Pharmaceutical and Medical lated Industries (PDA and DHI Publishing, LLC, 2006).
Devices Regulation Operations, pp.15 -17 (CRC Press, Boca Raton, 24. EU, Good Manufacturing Practice Medicinal Products for Human and Vet-
FL, 2017). erinary Use, Volume 4, Chapter 4: Documentation, Section 4.12. PT
11. NIST SP 800-33, “Underlying Technical Models for Information
Technology Security,” December 2001 (Withdrawn: August 2018).
12. FDA, Guidance for Industry-Process Validation: General Principles and
Orlando López has 30 years of experience in global
Practices (FDA, 2011).
pharmaceutical, and medical devices computer systems
13. L.T. Amy, Automation Systems for Control and Data Acquisition
regulatory compliance for companies that include
(ISA, 1992).
J&J, Allergan, Eli Lilly and Pfizer. He can be reached at
14. A Kane, Sidebar in A. Siew, “ Designing Optimized Formulations,”
[email protected].
Pharmaceutical Technology 41(4) (2017).

Regulatory Watch — contin. from page 14

FOR PERSONAL,
More structured assessments
NON-COMMERCIAL
on how an applicant controls Office of New Drugs, USE
quality. Too often, she said, the important gram. This includes reorganizing the
information
The modern drug assessment system developing new
under KASA will build on algorithms of risk “is lost in hundreds of pages of text.” IT platforms and applications, estab-
risk and support computer-aided analysis This may encourage a reviewer’s quality lishing quality metrics, and building
for a structured assessment of an applica- assessment to be more subjective, leading the emerging technology program to
tion. The process begins with an objec- to inconsistent decisions by the agency. promote new drug design and manu-
tive evaluation of risk that considers key Drug applications that present infor- facturing strategies. More consistent
critical quality attributes, enabling OPQ mation in prose require reviewers to do and objective regulatory assessments
staff to then focus on more risky products. “a lot of hunting and pecking” to pull out under KASA fits these broader goals by
The analysis considers the severity of pos- key data, added Mary Ann Slack, director helping FDA achieve more first-cycle
sible harms and the detectability of future of CDER’s Office of Strategic Programs. approvals for manufacturers and more
failures to be able to compare risks across To move forward, FDA plans to develop affordable and accessible medicines for
products and determine if attributes are and test electronic data standards for patients.
within or outside acceptable ranges. With submitting product quality and chemis-
such information, CDER still may ap- try, manufacturing, and controls (CMC) References
prove a risky product, but with a recogni- data to the agency, Slack explained. This 1. PQRI, 4th FDA/PQRI Conference on
tion of the need for greater oversight to will be described in draft guidance slated Advancing Product Quality, April 2019,
control for possible future problems. for publication by March 2020 to further https://pqri.org/4th-fda-pqri-confer-
In making the case for KASA at the explain how future applications should ence-on-advancing-product-quality-
PQRI meeting, OLDP Director Susan present data files that can be entered into presentations/
Rosencrance observed that applications FDA’s drug data system to check ranges 2. L. X. Yu et al., International Journal of
for new drugs and generics composed of and areas to review more closely. Pharmaceutics: X, 1 (December 2019),
unstructured text can be a hindrance to KASA is part of broader CDER efforts https://www.sciencedirect.com/science/
an efficient agency assessment of product to modernize its drug regulatory pro- article/pii/S2590156719300246 PT

38 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m

 Membrane-Based
Water for Injection
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Historically, distillation has been the most common technol- Presenters
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Gary V. Zoccolante 
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Analytics
associated variability and impact on safety,
pharmacokinetics, and pharmacodynam-
ics, glycosylation is widely regarded as a
critical quality attribute (CQA) of TGPs (1).
In the context of biopharmaceutical
quality assurance, 21 mathematical mod-
els for protein glycosylation have been de-
veloped over the past decade. Although the
strategies to mathematically describe the
glycosylation process have been diverse,
all models have demonstrated potential
toward addressing one or more quality as-
surance (QA) issues associated with TGP
manufacture. This review focuses on how
different modeling strategies can be lever-

Leveraging Computational aged to aid in product QA across the dif-

ferent stages of biopharmaceutical product
development and manufacture. Technical

Models of Glycosylation for details on glycosylation models have been

outlined elsewhere (6).

Biopharma QA Glycosylation impacts the safety

and efficacy of protein therapeutics
The following individual glycosylation
Ioscani Jiménez del Val motifs that are known to influence the
safety, pharmacokinetics, and pharmaco-
dynamics of TGPs are presented in Figure 1:
• Presence of high-mannose glycans,
Close collaboration between academic in particular, the five-mannose
and industrial groups is vital to ensuring glycan (Man5), reduces the serum
half-life of antibodies (7). Man5 may
glycosylation models are fit for deployment.
FOR PERSONAL, NON-COMMERCIAL USE also enhance antibody-dependent
cellular cytotoxicity (ADCC) (8), a

M
any of the highest-grossing protein the aforementioned biopharmaceuticals (2). mechanism that improves the onco-
therapeutics, including monoclo- Glycosylation is also widely acknowledged lytic activity of mAbs.
nal antibodies (mAbs), Fc-fusion as a major source of therapeutic protein • Tandem _-1,3 galactose is a non-
proteins (etanercept [Enbrel, Amgen/ heterogeneity (3), which is highlighted by human glycosylation motif that is
Pfizer] and aflibercept [Eylea, Bayer/Re- work that found considerable glycosylation produced by murine cell lines, such
generon]), interferon gamma (IFN-a), variation among different commercial lots as NS0 and Sp2/0 (9) and has also
erythropoietin (EPO), and tissue plas- of the same biopharmaceutical product (4). been observed in CHO cells (10).
minogen activator (tPA) contain complex Biopharmaceutical glycosylation vari- Presence of _-1,3 galactose residues
carbohydrates (glycans) covalently bound ability is determined by manufacturing has been reported to cause fatal
to their peptide backbone (1). In turn, the bioprocess conditions (1). Large-scale anaphylaxis in patients treated with
presence and relative abundance of dif- mammalian cell culture is used for the Cetuximab (Erbitux, Bristol-Myers
ferent glycan motifs (e.g., _-1,3 galactose, manufacture of all therapeutic glycopro- Squibb/Merck) (9,11). These cases oc-
core fucosylation, and sialylation) are well- teins (TGPs), with Chinese hamster ovary curred in patients who were allergic to
known to influence the safety, serum-half (CHO) and murine myeloma (NS0 and _-galactose, a condition likely caused
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life (pharmacokinetics), and the therapeu- Sp2/0) cell lines being the most-commonly by exposure to tick bites (9,11). To
tic mechanisms (pharmacodynamics) of used production platforms (5). During cell avoid these reactions, patients are now
culture, even subtle variations in nutrient screened for _-galactose allergy prior
availability, dissolved oxygen, tempera- to treatment with Cetuximab (9,11).
Ioscani Jiménez del Val is assistant ture, ammonia, and pH may impact the • The absence of core fucose has been
professor at the School of
Chemical & Bioprocess Engineering,
intracellular process of glycosylation (1,3) reported to enhance mAb ADCC
University College Dublin, Ireland, and yield product that cannot be admin- activity up to 50-fold in in-vitro
[email protected]. istered to patients. Due to its bioprocess- studies (12). Cell engineering strat-
40 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
 egies to eliminate core fucosylation serine or threonine residues on the pro- works involved in the process and were
have resulted in two commercially- tein backbone (19). After this first step, pioneered by Krambeck and Betenbaugh
available glycoengineered mAb the glycan is modified by a sequence of in 2005 (25). Building on these seminal
products, mogamulizumab (Po- enzyme-catalyzed monosaccharide ad- studies, more than 20 mathematical mod-
teligeo, Kyowa Kirin) and obinutu- dition reactions that extend its branching els for protein glycosylation have been de-
zumab (Gazyva, Roche). and length (19). CHO cells produce only veloped to date. Based on structure and
• High levels of `-1,4 galactosylation on two O-glycosylation variants, which con- solution strategy, the mathematical mod-
the Fc glycans of mAbs enhance their sist of the mono- and bi-sialylated ‘Core 1’ els of TGP glycosylation can be grouped
complement-dependent cytotoxicity structures shown in Figure 1 (20). into three categories: kinetic models, flux-
(CDC) (13) and ADCC (14). High For the purposes of this review, the gly- based models, and statistical models.
`-1,4 galactosylation is, therefore, a cosylation process is considered to have Kinetic models attempt to capture the
preferable attribute of oncolytic mAbs. two distinct inputs. The first encompasses time-dependent mechanisms underlying
• High levels of _-2,6 sialylation have the enzymes, which catalyze the monosac- glycosylation and are based on dynamic
been linked with enhanced anti-in- material balances for all TGPs and NSDs
flammatory activity in intravenous present in Golgi (26–28). Given the in-
immunoglobulin (IVIg) thera- … mechanistic herently dynamic nature of cell culture
pies (15) and would, thus, be a desir- processes, kinetic models are particularly
able attribute of immune-modulating models are, suited to describe the effects bioprocess
TGPs, such as adalimumab (Humira, conditions have on TGP glycosylation. A
AbbVie) and Enbrel. Importantly, conceptually, more fundamental drawback of kinetic models
the anti-inflammatory properties of is that they require a substantial amount
sialylation are exclusive to the glyco-
versatile than of experimental data to determine robust
sidic bond conformation (_-2,6) and
the sialic acid species (N-acetylneur-
their statistical values for their unknown parameters (e.g.,
enzyme kinetic rate constants).
aminic acid, Neu5Ac) involved (15). counterparts … Flux-based glycosylation models consist
CHO, NS0, and Sp2/0 cell lines only of material balances for all TGPs present
produce _-2,3 bonds and may also charide removal and addition reactions in the Golgi apparatus and are built using
produce sialylation with N-glycolyl (glycoenzymes). The second input for the reaction networks that define the produc-
neuraminic acid (Neu5Gc), a moiety glycosylation processes consists of nucleo- tion and consumption stoichiometry of
that may be immunogenic in hu- tide sugar donors (NSDs), which are me- each species. To solve flux models, steady
mans (16). Higher Neu5Ac sialylation tabolites that provide monosaccharides for state is assumed, and the resulting system

FOR PERSONAL, NON-COMMERCIAL USE

has also been reported to increase the
serum half-life of TGPs (17).
the sugar addition reactions of the glyco-
sylation process. NSDs are endogenously
of linear equations is solved for the rates
(fluxes) at which all TGPs are intercon-
synthesized by the production cell lines verted. Because the resulting system of lin-
Protein glycosylation using common nutrients, such as glucose ear equations is usually underdetermined
in mammalian cells and glutamine, as substrates (21). Thus, (more unknown fluxes than equations),
Protein asparagine (N)-linked glycosyl- NSDs are the direct link between cellular flux models must be solved using con-
ation occurs in two steps (18). The first metabolism (i.e., nutrient availability) and straint-based linear programming (29,30)
occurs while the protein is being synthe- TGP glycosylation. Many cell culture NSD or probabilistic methods, such as Markov
sized in the endoplasmic reticulum and precursor feeding strategies have been de- chain Monte Carlo simulations (31,32). A
entails the covalent addition of a large veloped to tune TGP glycosylation (22,23). key advantage of flux-based models is that
unprocessed precursor oligosaccharide their solution requires reduced amounts
to asparagine residues of the protein Models of therapeutic of experimental data. The main drawback
backbone. The glycoprotein is then trans- protein glycosylation (2009 to 2019) of flux-based models is that their solution
ferred, via vesicles, to the Golgi apparatus, The first model for N-glycosylation, pub- inherently assumes steady-state, which
where the second and final step of the N- lished in 1996, aimed to describe the addi- limits their ability to describe the dynamic
glycosylation process occurs: while tran- tion of glycans to the peptide backbone of shifts in TGP glycosylation often observed
siting through Golgi, the protein-bound proteins (24). From then, N-glycosylation in cell culture processes. This limitation
glycan is sequentially modified by several models expanded to include the extent of has been recently addressed by including
enzyme-catalyzed carbohydrate removal glycan processing within the Golgi ap- parameters representing dynamic shifts
and addition reactions. paratus, thus aiming to depict the vari- in TGP residence time within Golgi (30).
Serine/threonine (O)-linked glyco- ability observed in TGP glycosylation Statistical models are abstract black-box
sylation occurs entirely in the Golgi ap- profiles. Descriptions of glycosylation mathematical representations where pro-
paratus and begins with the addition soon required strategies for automati- cess inputs are quantitatively related, via
of N-acetylgalactosamine (GalNAc) to cally generating the complex reaction net- statistical regression strategies, with TGP
Pharmaceutical Technology JUNE 2019 41
Analytics
Figure 1. Glycans as therapeutic glycoprotein (TGP) quality attributes. glycoengineering, and statistical models
have been used for bioprocess character-
ization, control, and optimization. The
application areas for the different model-
ing strategies results from their underly-
ing features. Because kinetic models aim
to mechanistically describe the glycosyl-
ation process, they are capable of covering
all QA application areas. Flux models are
well-suited to define cell glycoengineer-
ing strategies because they focus on the
rates of glycoenzyme-catalyzed reactions.
By definition, statistical models quantita-
tively represent correlations between bio-
process conditions and TGP glycosylation.
Therefore, they are particularly adept for
bioprocess control and optimization QA
applications when mechanistic bioprocess
knowledge is lacking.
Although the deployment of statistical
models in industry is increasing at an ac-
celerated pace (49), the use of mechanistic
glycosylation models remains to be wide-
spread. This disparity may arise from the
use of specialized software and the per-
The Man5 glycan (A) reduces the serum half-life of TGPs (7) and may also yield ceived need for expert user input associ-
enhanced oncolytic activity (8). Tandem α1,3-linked galactosylation residues ated with mechanistic modeling. Despite
(B) may cause fatal anaphylaxis in certain patient populations (9,11). Absence of these challenges, mechanistic models are,
core fucose (12) and high β-1,4 galactosylation (13,14) (C) on the Fc glycans of conceptually, more versatile than their
monoclonal antibodies (mAbs) enhance their oncolytic activity. α-2,3 Nue5Ac statistical counterparts because they are
sialylation (D) increases TGP serum half-life (17). The O-linked glycans produced based on the biochemical mechanisms

FOR PERSONAL, NON-COMMERCIAL USE

by Chinese Hamster Ovary (CHO) cells are limited to mono (E) or bi-sialylated
(F) Core 1 structures (20) that also influence TGP quality. Symbols representing
underlying the glycosylation process. An
interesting example where these limita-
the monosaccharides, which constitute TGP glycans, are shown at the bottom. tions are addressed is the GLYMMER
(ReacTech) software platform, which is
based on the work by Bennun et al. (37),
glycosylation profiles. Examples of statis- and highlights how each model has been runs on Microsoft Excel, and requires
tical models of TGP glycosylation are de- used toward potential TGP quality assur- only moderate user input and expertise.
sign of experiment (DoE) surface response ance applications.
models (23) and partial least squares re- Conclusion
gression (33,34). Advantages of statisti- Deployment of glycosylation The deployment of different glycosylation
cal models are that they do not require a models for biopharmaceutical QA modeling strategies depends entirely on
priori knowledge of the process, require Table I shows that all published gly- the TGP quality assurance application
little or no end-user modeling expertise, cosylation models have been used for they will be used for. Statistical models
and can therefore be deployed with rela- applications that can directly support can be readily deployed in the industrial
ALL FIGURES ARE COURTESY OF THE AUTHOR

tive ease. Statistical models are limited in TGP QA practices. Four QA applica- setting for bioprocess design, control, and
that they are exclusively data-driven and, tion areas stand out: (i) data analytics, optimization (33,43) with minimal user
thus, are unable to yield insight into the (ii) bioprocess characterization, (iii) cell input and expertise. Mechanistic models
mechanisms underlying TGP glycosyl- line engineering/development, and (iv) (kinetic and flux-based) have been shown
ation. Furthermore, the predictive capabil- manufacturing bioprocess optimization to be particularly robust for cell line char-
ity of statistical models may break down if and control (21,23,26,27,29–48). acterization (27,50) and glycoengineer-
model inputs drift outside the input space Kinetic models appear to be the most ing (26,31) as well as for bioprocess design
with which they were calibrated. versatile, having been used for all four ap- and optimization (42,47).
Table I presents the glycosylation mod- plication areas. Flux-based models have To fully exploit the advances in glyco-
els that have been developed since 2009 mainly focused on cell line selection and sylation modeling toward the develop-
42 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
Table I. Mathematical models of protein glycosylation (2009–2019).
Therapeutic glycoprotein (TGP)
Study Year Model type
glycosylation quality assurance (QA) applications
Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)
Krambeck et al. I (35) 2009 Kinetic
glycan data analysis for cell line characterization.
del Val et al. (36) 2011 Kinetic In-silico cell line glycoengineering.
MALDI-TOF glycan and transcriptomic data analysis for cell line
Bennun et al. (37) 2013 Kinetic
characterization.
Design of experiments (DoE) surface response model for at-line
Grainger & James (23) 2013 Statistical
bioprocess control.
Predicts dynamic variations in monoclonal antibody (mAb) glycans for
Ohadi et al. (38) 2013 Kinetic
bioprocess characterization.
Predicts dynamic variations of mAb glycans from extracellular nutrient
Jedrzejewski et al. (21) 2014 Kinetic
availability for bioprocess characterization.
Hang et al. (29) 2015 Flux-based Glycan data analysis for protein and cell line characterization.
Predicts dynamic variations of mAb glycans for bioprocess characterization,
del Val et al. I (26) 2016 Kinetic
cell line selection and in-silico glycoengineering.
Defines the nucleotide sugar donor (NSD) demand towards cellular
del Val et al. II (39) 2016 Reconstruction
glycosylation for cell line characterization and bioprocess control.
Automated framework for O-glycosylation reaction network reconstruction
McDonald et al. (40) 2016 Reconstruction
for cell line characterization.
Spahn et al. (31) 2016 Flux-based In-silico Chinese hamster ovary (CHO) cell line glycoengineering.
Predicts dynamic variations of mAb glycans from cell culture conditions for
Villiger et al. (41) 2016 Kinetic
bioprocess characterization and control.
Predicts dynamic variations of mAb glycans from manganese
Hutter et al. (30) 2017 Flux-based
supplementation for bioprocess characterization and control.
Kinetic & Compares kinetic and statistical models for perfusion bioprocess
Karst et al. (42) 2017
Statistical optimization and control.
MALDI-TOF glycan and transcriptomic data analysis for cell line
Krambeck et al. II (27) 2017 Kinetic
characterization and in-silico cell line glycoengineering.

FOR PERSONAL, NON-COMMERCIAL USE

Used to design cell culture media to achieve glycosylation biosimilarity of a
Sokolov et al. I (43) 2017 Statistical
mAb (bioprocess optimization and control).
Predicts dynamic variations of mAb glycans from cell culture conditions for
Sokolov et al. II (34) 2017 Statistical
bioprocess characterization and control.
Predicts dynamic variations of mAb glycans from cell culture conditions for
Sou et al. (44) 2017 Kinetic
bioprocess characterization and control.
Spahn et al. (32) 2017 Flux-based In-silico CHO cell line glycoengineering for glycosylation biosimilarity.
Kinetic+flux- Predicts galactosylation from cell culture conditions for bioprocess
Aghamohseni et al. (45) 2017
based characterization and control.
Kremkow & Lee (46) 2018 Flux-based In-silico CHO cell line glycoengineering.
Predicts dynamic variations of mAb glycans from cell culture conditions for
Sokolov et al. III (33) 2018 Statistical
bioprocess characterization and control.
Used to design an optimal NSD precursor feeding strategy that maximizes
Kotidis et al. (47) 2019 Kinetic
mAb galactosylation while maintaining product titer.
Automated framework for O-glycosylation reaction network reconstruction/
Le et al. (48) 2019 Reconstruction
visualization for cell line characterization.

ment, control, and optimization of next- References 4. A. Planinc, et al., Eur. J. Hosp. Pharm. Sci.
1. P. Zhang, et al., Drug Discov. Today 21 (5) Pract. 24 (5) 286–292 (2017).
generation TGP production bioprocesses, 5. A.L. Grilo and A. Mantalaris, Trends Bio-
close collaboration between academic 740–765 (2016).
2. L. Liu, J. Pharm. Sci. 104 (6) 1866–1884 technol. 37 (1) 9–16 (2019).
and industrial groups must continue so (2015). 6. C. Kontoravdi and I.J. del Val, Curr. Opin.
that the models are fit for purpose and 3. J. Fournier, Biopharm Int. 28 (10) 32–37 Chem. Eng. 22 89–97 (2018).
require minimal end-user expertise for (2015).
deployment. contin. on page 46

Pharmaceutical Technology JUNE 2019 43

Supply Chain
“Supply chain security is a core end-
to-end capability in a business to ensure
that all products reaching the patient are
safe, compliant, and delivered on time
and in full,” adds Roddy Martin, chief
digital strategist, TraceLink. “Most im-
portantly, the elements of risk and se-
curity are proactively tracked across the
end-to-end business so that any devia-
tions are detected quickly and responded
to, without impacting the continuity of
supply or impacting patient safety.”
Security of the supply chain is criti-
cal for all companies that offer products
and services to consumers, concurred
Ettore Cucchetti, CEO of ACG Inspec-
tions, particularly in terms of counterfeit
products, product damage or theft, and

On the smuggling. “For the pharmaceutical in-

dustry, which is dealing with products
and services directly impacting human

Right Track health, supply chain security becomes

more crucial in terms of a company’s
product integrity, brand image, and, ul-
Felicity Thomas timately, its bottom line,” he says.

Different approaches
As Michael Pisa and Denise McCurdy re-
Proactive approaches that consider ported in their policy paper in February
long-term supply chain security 2019, at a basic level there are two trace-
ability models that can be adopted (3).

FOR PERSONAL, NON-COMMERCIAL USE

compliance are recommended to
ensure companies stay on the right track.
One model is to have a point-of-dispense
verification approach where verification
occurs at the top of the supply chain and
then also at the bottom. The other model

D
espite there being various terms billion to $217 billion) per year (2). is full traceability, which is more com-
used, counterfeit, falsified, fake, and Given the size of the market and the plex in nature as the tracking and trac-
so on, a drug that has been fraudu- risk to patient health, many authorities ing of products occurs every time they
lently manufactured and distributed to have been implementing regulations to change hands within the supply chain.
mimic an authorized medicine, whether protect the security of the supply chain. Many countries and regions have al-
branded or generic, poses significant “The proliferation of online pharma- ready signed a traceability approach into
risks to companies and, more impor- cies, and the Internet in general, has law, including China, India, Turkey, the
tantly, to patient health. The World meant that the pharmaceutical black- European Union, and the United States,
Health Organization (WHO) estimates market has trickled into mainstream and approaches vary from country-to-
that one in 10 medical products are sub- society and consequently become a country. “Verification and full trace-
standard or falsified in low- to middle- widespread issue,” asserts Staffan Wid- ability can both facilitate and improve
income countries, based on a literature engren, director corporate projects, Re- supply chain security,” says Widengren.
review of previously published papers (1). cipharm. “As a result, health regulators The EU and US, for example, chose
GRIBANOV - STOCK.ADOBE.COM

In financial terms, as reported by have established new legislation and the adopt different approaches. The
Strategy&, PricewaterhouseCoopers’ surveillance strategies around supply former employing the point-of-dis-
strategy consulting business, falsified chains in a bid to prevent and minimize pense verification approach, while the
medicines represent a lucrative pro- the circulation of falsified drugs. With- latter is using the full traceability ap-
portion of illicit goods sold within the out supply chain security measures, we proach. “In the EU market, serializa-
global market, estimated to range from cannot effectively track or determine tion requirements were implemented
€150 billion to €200 billion (US$163 the legitimacy of a drug product.” as part of the falsified medicines direc-
44 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
 tive (FMD) regulation to protect the
safety of patients,” adds Widengren.
Supply chain risk and security maturity evolution
“Essentially, through serialization, dis-
pensers gain the ability to verify prod- Discussing supply chain risk and security as a • Stage 4. Supply chain and risk are codified as
uct legitimacy before a drug reaches business led journey, Roddy Martin, chief digital core ‘this is how we work’ requirements in all
the patient by scanning the unique strategist at TraceLink, explains the five stages of horizontal, end-to-end, and cross-functional
identifier included on the pack. its evolution to Pharmaceutical Technology: processes from the patient all the way back
“Whereas, track-and-trace systems • “Stage 1. Reacting to risk and security problems through the business into all elements of
can not only determine the authentic- after the fact. supply.
ity of a product at the point of dispense, • Stage 2. Specialized security and risk • Stage 5. Risk and security capabilities are
but also track the movement of prod- management projects; for example, track and embedded into and across the total ecosystem
ucts and prohibit falsified medicines trace/serialization. and network both internal and external to a
from progressing through the supply company; the core capability is that product
• Stage 3. Supply chain risk and security are a
chain,” he continues. “Each partner in- integrity, availability, and patient safety are
functional excellence capability; for example,
volved in getting drugs to market can regarded as a given. In stage 5, risk and security
risk and security requirements are codified into
scan unique identifiers to access data are both driven as value based capabilities
all work within functions like manufacturing,
around the journey of medicines and rather than seen as a cost.”
procurement, logistics, and so on.
verify the authenticity of medicines as
they move through the supply chain.”
Additionally, Martin emphasizes ing technologies for securing supply
Dealing with data that as industry looks to the future chains,” notes Ettore Cucchetti. “Each
Each traceability approach being imple- and leveraging the data gained from regulatory body has multiple objec-
mented across the world has inevitably serialization, there will be a shift away
tives, but the preliminary goal remains
impacted industry, in particular as a re- from the fragmented silo nature of the the same—to secure the product from
sult of the need to deal with vast amounts bio/pharma supply chain that has ex- manufacturer to end consumer.”
of data. “Due to the sheer amount of data isted previously as a fractious supply Giving some examples, Cucchetti
generated by serialization requirements, chain hinders visibility and impacts highlights Russia, which has mandated
organizations have been required to eval- performance. “Instead, serialization crypto tail into barcoding processes;
uate and adopt software technology solu- should be used as a lens to look at the Indonesia, which is assessing product
tions to create, capture, store, report, and end-to-end digital supply chain and, if authentication techniques; and the US,
share compliance data at scale,” notes done right, will lead to transformative which is looking to evaluate block-

FOR PERSONAL, NON-COMMERCIAL USE

Martin. “This question of technology
scalability remains a real concern when
benefits in terms of increasing busi-
ness value through more collaborative
chain with serialization. “Currently,
most of the regulatory requirements
it comes to simply meeting the require- supply chains and end-to-end visibility are focused towards serialization and
ments of these legal mandates them- into value networks,” he explains. track and trace, as well as mandates for
selves, which is one of the critical reasons “Blockchain will be considered as one the pharmaceutical industry,” he says.
that a cloud-based, network platform is of the critical factors when it comes to
“Going forward, it is likely that simi-
optimal,” he continues. selecting a supply chain partner in the lar regulations will be applicable to all
In agreement, Widengren states that future,” adds Cucchetti. “Product trace-other industries as well. Government
cloud-based networks have been found ability and recalls are known to be the and regulatory bodies will be more
to be the most successful in terms of biggest challenges for most industries, stringent in regulation—considering
connecting supply chain partners and and blockchain landscape can be used consumer health and safety require-
enabling the exchange of serialization to secure the transaction between the ments. As the technologies evolve, each
data. “As well as enabling compliance supply chain partners. With blockchain, government will be evaluating possi-
with serialization regulations, these companies can address counterfeit is- ble technological implementations to
platforms also offer the opportu- sues through the authentication process,secure supply chains to fight against
nity for businesses to improve supply and they can perform product recall counterfeiters, and also to have com-
chain visibility and gain additional smoothly. This can help them to iden- plete visibility of the industry.”
value from their investment,” he says. tify the issues in logistics and distribu- Specifically focusing on the US and
“By giving companies greater insight tion channels, using the complete supplyits exploration of methods to enhance
into their operations, businesses can chain data to optimize the supply chain.”
the safety and security of the supply
make more informed decisions in areas chain, Martin discusses FDA’s Drug
such as supply and demand forecast- Regulatory initiatives Supply Chain Security Act (DSCSA)
ing, product recalls, and even achieve “Regulatory and government bodies are pilot program. “Recently, FDA an-
engagement with patients.” looking into all available and emerg- nounced a pilot program project
Pharmaceutical Technology JUNE 2019 45
Supply Chain
seeking innovative and emerging ap- landscape is in a state of flux,” emphasizes upcoming changes and work towards
proaches for enhanced tracing and ver- Widengren. “It is essential to consider accommodating them.”
ification of prescription drugs in the long-term prospects so that a plan can As a final note, Widengren explains
US to ensure suspect and illegitimate be made around new legalities. As such, that for companies to be able to reap the
products do not enter the supply chain,” pharmaceutical manufacturers should in- benefits of supply chain security require-
he confirms. “TraceLink was accepted vest time into understanding the markets ments and for optimum preparedness
into the pilot program and will focus they operate in, as well as the ones they and future safeguarding, companies
on two workstreams; blockchain and may potentially pursue. This way they can should consider implementing aggrega-
digital recalls.” design a strategy that will help facilitate tion capabilities. “Aggregation is not al-
Companies of varying sizes will be market entry and progression with as ways a mandatory measure,” he summa-
included in the TraceLink pilot project, little complexity and limitation possible.” rizes, “but it is expected to become part
covering the end-to-end supply chain. For Cucchetti, a proactive approach of legislative requirements in the future.”
“Together, through network connectiv- to supply chain security is key as it
ity and innovative software solutions, can afford companies time to be able References
participants will explore and collabo- to adapt to all changes required when 1. WHO, “A Study on the Public Health and
rate on ways to improve the safety and complying with regulations. “Compa- Socioeconomic Impact of Substandard
and Falsified Medical Products,” Report,
security of the drug supply chain and nies should form a dedicated team with November 2017.
will use early stage technology to do all business functions involved in the 2. Strategy&, “Fighting Counterfeit Pharma-
so,” Martin adds. serialization project, documenting all ceuticals New Defenses for an Underesti-
regulatory and business requirements,” mated—and Growing—Menace,” Report,
Safeguarding future supply chains he says. “At all times, organizations June 29, 2017.
3. M. Pisa and D. McCurdy, “Improving
“Companies should always be mindful of should work alongside the implemen- Global Health Supply Chains Through
new ways they can safeguard their sup- tation partner and possibly with the Traceability,” Center for Global Develop-
ply chains, especially when the political regulation bodies to understand the ment Policy Paper 139, February 2019. PT

Analytics — contin. from page 43

References cont. 20. S. Houel, et al., Anal. Chem. 86 (1) 36. I.J. del Val, J.M. Nagy, and C. Kontoravdi,
7. A.M. Goetze, et al., Glycobiology 21 (7) 576–584 (2014). Biotechnol. Prog. 27 (6) 1730–1743 (2011).
949–959 (2011). 21. P.M. Jedrzejewski, et al., Int. J. Mol. Sci. 15 37. S.V. Bennun, et al., PLoS Comput. Biol. 9 (1)
8. M. Yu, et al., MAbs 4 (4) 475–87 (2012). (3) 4492–4522 (2014). e1002813 (2013).

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9. J.W. Steinke, T.A. Platts-Mills, and S.P.
Commins, J. Allergy Clin. Immunol. 135
22. N.S. Wong, et al., Biotechnol. Bioeng. 107 (2)
321–336 (2010).
23. R.K. Grainger and D.C. James, Biotechnol.
38. K. Ohadi, et al., IFAC Proceedings Volumes
46 (31) 30–35 (2013).
39. I.J. del Val, K.M. Polizzi, and C. Kontoravdi,
(3) 589–596 (2015).
10. C.J. Bosques, et al., Nat. Biotechnol. 28 (11) Bioeng. 110 (11) 2970–2983 (2013). Sci. Rep. 6 28547 (2016).
1153–1156 (2010). 24. M. Shelikoff, A.J. Sinskey, and G. Stepha- 40. A.G. McDonald, K.F. Tipton, and
11. T.A. Platts-Mills, et al., Immunol. Allergy. nopoulos, Biotechnol. Bioeng. 50 (1) G.P. Davey, PLoS Comput. Biol. 12 (4)
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3466–3473 (2003). technol. Bioeng. 92 (6) 711–728 (2005). 3–12 (2016).
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69–75 (2016). e0175376 (2017). 181–191 (2017).
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373-376 (2008). 1135–1148 (2016). 1570–1582 (2017).
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(1995). 1335–1349 (2015). Biotechnol. 44 (7) 1005–1020 (2017).
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2343–2351 (2015). 9–20 (2017). 47 134–142 (2018).
18. P. Stanley, N. Taniguchi, and M. Aebi, “N- 31. P.N. Spahn, et al., Metab. Eng. 33 47. P. Kotidis, et al., Biotechnol. Bioeng. In press
Glycans”, in Essentials of Glycobiology, A. 52–66 (2016). (2019) DOI: 10.1002/bit.26960.
Varki, et al., Eds., pp. 99–111, (Cold Spring 32. P.N. Spahn, et al., Biotechnol. J. 12 (2) (2017). 48. T. Le, et al., Biotechnol. Bioeng. In press
Harbor, New York, NY, 2nd ed., 2015). 33. M. Sokolov, et al., Biotechnol. J. 13 (4) (2019) DOI: 10.1002/bit.26952.
19. I. Brockhausen and P. Stanley, “O-GalNAc e1700461 (2018). 49. P. Kroll, et al., Pharm. Res. 34 (12)
Glycans”, in Essentials of Glycobiology, A. 34. M. Sokolov, et al., Biotechnol. Prog. 33 (5) 2596–2613 (2017).
Varki, et al., Eds., pp. 113–123 (Cold Spring 1368–1380 (2017). 50. S.V. Bennun, et al., J. Mol. Biol. 428 (16),
Harbor, New York, NY, 2nd ed., 2015). 35. F.J. Krambeck, et al., Glycobiology 19 (11) 3337–3352 (2016). PT
1163–1175 (2009).

46 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m

Good Laboratory Practices
reproduced, a problem that contin-
ues to delay the development of new
products and wastes $28 billion/year
in the United States alone (2).
In some cases, researchers found,
equipment was not being used effi-
ciently based on vendor guidelines;
in others, biological reagents and
reference materials, cell lines, anti-
bodies, and reagents were not prop-
erly validated (3). Also faulted were
incomplete study data and lab pro-
tocols.

Improving data access

Industry executives have pointed to
cross-functional data access and uti-
lization as a major challenge for the

Good Laboratory Practices: industry. This challenge affects the

lab as well as the plant. IDC Health
Insights surveyed 126 biopharma-

Getting on the Same Page ceutical and pharmaceutical execu-

tives in the United Kingdom and the
US, and found a significant gap be-
Agnes Shanley tween their need and their strategies
for harnessing data (4). More than
98% of respondents said that cross-
functional data access was important
Quality and compliance depend on the or very important to their business
strategies, and 94% described the
right approaches to training, standard ability to apply advanced analy t-

FORprocedures,
operating PERSONAL, NON-COMMERCIAL
and validation. More USE ics and/or artificial intelligence the
same way. However, 51% of those
tools are available to help ensure success. surveyed said that they did not have
a clear strategy in place to help them
reach either of those goals.

L
ike many crucial regulations, quality-control labs approach data A number of digital tools are avail-
good laboratory practices (GLPs) integrity, training, and SOPs. Incor- able to help lab scientists capture and
were enacted in 1979 after FDA rect approaches to investigating OOS use more data, to improve laboratory
observers found serious problems in conditions are also frequently found efficiency and reproducibility. These
documentation, training, and data in regulatory citations, for GLPs as tools allow data to be extracted from
integrity at a number of research labs well as for good manufacturing prac- various software systems, and some
(1). Global GLPs establish guidelines tices (GMPs). of them feature use of machine lan-
for standard operating procedures guage and elements of artificial in-
(SOPs), which explain how to carry Lack of reproducibility telligence. One example is LabStep,
out specific tests and how to use Another major problem that can be an interactive digital platform de-
and maintain laboratory equipment. traced to inadequate compliance with signed to help scientists get around
GORODENKOFF - STOCK.ADOBE.COM

GLPs also set requirements for equip- GLPs is lack of reproducibility (i.e., a some of the deficiencies of electronic
ment calibration and maintenance, situation in which other laboratories lab notebooks (ELNs). The platform
data collection, and investigation cannot replicate the results published allows users to refer directly to the
and documentation of out-of-speci- in original research conducted in an most relevant protocols, SOPs, and
fication (OOS) findings. innovator laboratory). In 2015, the other important data (5) as they work.
Decades later, global regulators Global Biological Standards Institute LabTwin is also active in this area,
still find deficiencies in the way that (GBSI) found that 50% of published and will introduce a new voice-acti-
some companies’ preclinical and preclinical research could not be vated lab assistant at BIO 2019 in June,
Pharmaceutical Technology JUNE 2019 47
Good Laboratory Practices
in Philadelphia. Combining artificial Training is a challenge PharmTech: Reproducibilit y is a
intelligence, voice recognition, and PharmTech: How do you recommend major problem for biopharmaceutical
machine language, the hands-free that biopharmaceutical companies preclinical research. Is this problem
device allows researchers to docu- tackle training? also seen in pharma quality control
ment steps they have taken and to save Jones: Initial training, especially labs? What best practices do you rec-
explicit details that cannot currently with newer employees, can be done ommend regarding the validation of
be saved in ELNs (6). Labfolder (7) is through reading, lecture, and/or some materials and methods?
yet another platform that has been type of knowledge or learning assess- Jones: We have found that, after re-
designed to enable more laboratory ment, but the best results occur when search and development of the method
data to be saved, accessed, and used that theoretical work is followed up by our R&D scientists, it is important
throughout any organization. and supplemented by hands-on train- to involve the sample analysis team
in performing some, if not all, of the
validation experiments, with techni-
“It is important to involve the sample cal assistance provided, as needed, by
the R&D scientists who developed
analysis team in performing some, if not the method. This approach allows
for a shared collaboration between
all, of the validation experiments, with the research and production teams,
and continues into sample analysis to
technical assistance provided by the R&D ensure reproducible results from the
scientists who developed the method. developed and validated method.
Best practices include following the
— Stuart Jones, PPD Laboratories proper bioanalytical method valida-
tion guidances; the bridging of critical
reagents; analyst method qualification
Ultimately, compliance with GLPs ing. This is accomplished most effec- and scientific expertise/knowledge
depends on following best practices. tively by teaming new employees with of the assay; as well as the use of in-
Stuart Jones, regulatory quality as- experienced staffers, using training curred sample reproducibility testing
surance professional in good labora- goals established within a predeter- as one of the ways that the bioanalyti-
tory practice (RQAP-GLP) and di- mined curriculum. cal lab can prove that the method can
rector of quality assurance at PPD Some measure of refresher training be reproduced.

FOR PERSONAL, NON-COMMERCIAL USE

Laboratories’ Bioanalytical Labora-
tory shared recommendations with
should be required on at least an an-
nual basis and it should be consistent References
Pharmaceutical Technology. across all experience levels. Metrics 1. H.Danan, Pharmaceutical Technology
generated around unplanned protocol 15(6), (2003).
2. L. Freedman et al, BioPharm Interna-
Best practices and SOP deviations, as well as human
tional 28(10) pp 14-21 (2015).
PharmTech: What GLP problems do error, should be used as indicators in 3. M. Williams, Current Protocols 81(1)
you frequently encounter at pharma determining the course and effective- (2018).
and biopharma companies, and how ness of current training plans. 4. Accenture, “The Case for Connectivity
can they be prevented? in the Life Sciences,”Infographic, accen-
Jones: Because we work in such a Destroying silos ture.com, May 22, 2019, www.accenture.
regulated environment, a seemingly PharmTech: What best practices do you com/_acnmedia/PDF-101/Accenture-
INTIENTInfographic-IDC.pdf.
minor matter can have a significant recommend to make data less siloed
5. Lab Twin, Press Release, “Voice Acti-
impact on quality. As such, training and more accessible to those who may vated Laboratory Assistant to Launch
is an important best practice, from need it (on cross functional teams?) at BIO 2019,” www. scrip.pharmaintel-
the time of hire, to retraining when a Jones: One of the best ways to estab- ligence.informa.com/SC125243/Lab-
deviation occurs. lish a more cross-functional approach Twin-Voice-Activated-Lab-Assistant-
Annual refresher training as well and enhance data accessibility is to To-Launch-At-Bio
as specific group remedial training use one system across all sites. If one 6. J. Gould, “How Technology Can Help
Solve Science’s Reproducibility Crisis,”
should also be provided whenever across-the-board system is not pos-
April 25, 2019, w w w.nature.com/ar-
needed. Meanwhile, the use of auto- sible, then the multiple systems must ticles/d41586-019-01333-0#MO0.
mated or electronic systems, such as be able to work in tandem. Data por- 7. S. Bungers, “The Electronic Lab Note-
laboratory e-notebooks, can be espe- tals and SharePoint sites also can be book in 2019,” labfolder.com, www.lab-
cially beneficial in maintaining the utilized to securely share information folder.com/electronic-lab-notebook-
most accurate documentation. on a real-time basis. eln-research-guide/ PT

48 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m

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Ask The Expert— contin. from page 50

Taking the time to establish a quality agreement and investigate 6. FDA , G u i d a n c e f o r I n d u s t r y, I n v e s t i g a t i n g O u t- o f -
the details of their OOS procedure is the first step in establishing a Specification (OOS) Test Results for Pharmaceutical
good working relationship with your contract test laboratory. This Production (FDA, October 2006). PT

FOR PERSONAL, NON-COMMERCIAL USE

working relationship will become invaluable when an OOS occurs.
Your opinion matters.
The final product testing procedure for OOSs isn’t the only one
you need to review, however. You should also look at the quality Have a common regulatory or compliance question?
agreement and OOS procedure being used by your manufacturer Send it to [email protected] and it
may appear in a future column.
for in-process test results, assuming they are different entities.
The same information required in the final product OOS procedure
should be the same for in-process testing.

References
1. 21 CFR 200.10 (b)
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COMPANY PAGE
2. FDA, Contract Manufacturing Arrangements for Drugs: Quality
Arrangements: Guidance for Industry (FDA, November 2016).
Binswanger Management Corp............................................................ 31
3. European Commission, The Rules Governing Medicinal
Catalent Pharma Solutions ................................................................... 52
Products in the European Union, Volume 4, EU Guidelines
Evoqua Water Technologies LLC .......................................................... 39
for Good Manufacturing Practice for Medicinal Products for
KCAS ........................................................................................................ 17
Human and Veterinary Use, Chapter 7, Outsourced Activities
Labvantage Solutions, Inc ..................................................................... 33
(EC, January 31, 2013).
Ligand ........................................................................................................ 7
4. EC, EudraLex, The Rules Governing Medicinal Products in
Lonza Biologics ......................................................................................... 2
the European Union, Volume 4, EU Guidelines for Good
Lubrizol .................................................................................................... 23
Manufacturing Practice for Medicinal Products for Human
Master Control Systems ........................................................................ 15
and Veterinary Use, Part 1, Chapter 6: Quality Control (EC,
PDA ...................................................................................................... 3, 11
October 2014).
Perfex Corp ............................................................................................. 13
5. EC, EudraLex, The Rules Governing Medicinal Products in
Ross Mixers............................................................................................. 49
the European Union Volume 4, Good Manufacturing Practice,
Sartorius Stedim NA Inc........................................................................... 9
Medicinal Products for Human and Veterinary Use, Part II: Basic
Suheung-America Corporation ............................................................ 21
Requirements for Active Substances used as Starting Materials
Veltek Associates ..................................................................................... 5
(EC, September 2014).
Pharmaceutical Technology JUNE 2019 49
ask the expert

Quality Agreements and

Out-of-Specification
Investigations

A good working relationship between sponsor and contractor will become

invaluable when an OOS occurs, says Susan J. Schniepp, executive vice-president
of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.

Q. I’m responsible for quality at a small, virtual startup com-

pany, and we contract out all of our activities. I’m working
or significant negative trend, affecting product batches released
on the market should be reported to the relevant competent
on documentation to contract out our product testing and was authorities. The possible impact on batches on the market should
wondering what information there is regarding quality agree- be considered in accordance with Chapter 8 of the GMP Guide
ments and laboratory investigations. and in consultation with the relevant competent authorities” (4).
Part 2 of the EU GMP guide for APIs states in section 11.15 that:

A. The best place to start is to take a critical look at existing

guidance documents and regulations that govern quality
agreements and out-of-specification (OOS) investigations.
“Any out-of-specification result obtained should be investigated
and documented according to a procedure. This procedure
should require analysis of the data, assessment of whether a
The basic philosophy when establishing any quality agreement significant problem exists, allocation of the tasks for corrective
is to understand that the contract provider and contract giver are actions, and conclusions. Any re-sampling and/or retesting after
partners and their behaviors reflect on each other. The 21 Code OOS results should be performed according to a documented
of Federal Regulations (CFR) 200.10(b) confirms this concept by procedure” (5).
stating: “The Food and Drug Administration is aware that many T h e b e s t g u i d a n c e, h o w e v e r, o n c o n d u c t i n g O O S
manufacturers of pharmaceutical products utilize extramural investigations is the information provided in FDA’s Guidance
independent contract facilities, such as testing laboratories, for Industry, Investigating Out-of-Specification (OOS) Test

FOR PERSONAL, NON-COMMERCIAL USE

contract packers or labelers, and custom grinders, and regards Results for Pharmaceutical Production (6). The responsibilities
extramural facilities as an extension of the manufacturer’s own for the laboratory analyst and supervisor are clearly defined
facility” (1). The next document to review for quality agreements in this guidance and should be reflected in any laboratory
is the FDA guideline titled Contract Manufacturing Arrangements OOS procedure. A well-written standard operating procedure
for Drugs: Quality Agreements. Section B, Elements of a Quality (SOP) on OOSs should require investigations to be thorough,
Agreement, Part e. Laboratory controls states that a quality timely, unbiased, well documented, and scientifically sound.
agreement should include: “Designation of responsibility for Often, the procedure will contain a checklist that assists in
investigating deviations, discrepancies, failures, out-of- identifying obvious laboratory errors. The checklist assesses
specification results, and out-of-trend results in the laboratory, the suitability of analyst qualification and training, use of correct
and for sharing reports of such investigations” (2). This confirms procedure and specification, the calibration and performance
that the responsibility for OOS investigations is shared and of the equipment, correct preparation of test solutions and
communication between the contract giver and contract provider dilutions, use of proper reagents and standards, calculations, etc.
is critical. The European Union also addresses the need for a A thorough checklist and analyst documentation are critical in
relationship between you and your outsourced laboratory in identifying true laboratory error. The SOP should also discuss the
EudraLex, x Chapter 7 (7.15) on Outsourced Activities by stating: sample retesting requirements when a true laboratory error is
“The Contract should describe clearly who undertakes each determined to be the cause of the OOS.
step of the outsourced activity, e.g. knowledge management, The most important and critical element for OOS investigations
technology transfer, supply chain, subcontracting, quality is specifying the timeliness. This should be stipulated in the
DAMIAN PALUS/SHUTTERSTOCK.COM

and purchasing of materials, testing and releasing materials, SOP and, in most cases, the investigation into the OOS, from
undertaking production and quality controls (including in-process the laboratory perspective, should be concluded in 24 hours or
controls, sampling and analysis)” (3). less. The expectation of when the contract lab will inform you
The above regulations establish the need for qualit y of any OOS obtained should be clearly defined in your quality
agreements that cover laboratory activities but doesn’t define agreement. The sooner a laboratory error can be ruled out as the
what needs to be in an OOS procedure. The EU addresses the cause of the OOS result, the sooner the full-blown manufacturing
need to investigate OOSs in their GMPs. EudraLex x Part 1, Section investigation can be started.
6.35 states, “Out-of-specification or significant atypical trends
should be investigated. Any confirmed out of specification result, Contin. on page 49
50 Pharmaceutical Technology JUNE 2019 P h a r mTe c h . c o m
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