1.

Reducing Cleanroom Complexities and Cost

Why shouldn’t biopharmaceutical manufacturers be able to leverage standardized construction
practices to improve time to market?
Aug 01, 2018
By Sidney Backstrom, Maik W. Jornitz
Pharmaceutical Technology
Volume 2018 Supplement, Issue 3, pg s26–s28

ESB PROFESSIONAL/SHUTTERSTOCK.COMFor pharmaceutical and biopharmaceutical

manufacturers today, a key success factor is time to market (1–4). When it comes to processes
and manufacturing facilities, time to the first product run is crucial. The faster a drug moves
through the development pipeline and the faster a facility is up and running, the higher the return
on investment. In addition, a fast-moving facilities project can allow capital expenditures to be
delayed until later in the development cycle, minimizing risks and maximizing the amount of
cash on hand until needed.
The traditional approach

Traditional facility designs and infrastructures do not permit such fast-track implementation (5).
It takes months to generate designs and even longer to build these manufacturing sites, and
construction proceeds sequentially.

The process generally follows this pattern: a building shell is built first, followed by utilities,
then ancillary and cleanroom spaces, and finally production equipment is installed. Typically,
this approach means a time-to-first-product run of 24–48 months, depending on the size of the
facility. The same is true for smaller projects such as laboratories.

Modular options

Modular construction onsite involves building processing space at the ultimate production
location using modular wall panels. Many companies provide such panels. This approach differs
from traditional construction in that the panels are rigid and therefore do not require framing
material. The panels also come in a variety of sizes, reducing the amount of cutting required
onsite.

The panels also reduce the amount of finishing work that is required, because they are supplied
as finished pieces such as coving at the wall-to-ceiling and wall-to-floor connection points. The
use of standardized components can shorten the design phase for modular panel projects,
compared with the time required by traditional approaches. Significant engineering knowhow is
still required, however, to make modular construction work.

Because this approach reduces the amount of onsite construction required, these projects can be
completed faster than a traditional construction approach, with project timelines that can range
from 18 to 36 months depending on the size of the project.

Prefabricated cleanrooms

Prefabricated cleanrooms are modules that are built offsite that provide clean space including
floors, walls, ceilings, windows, and doors in appropriate finishes. In some instances, such
modules include their own mechanical space where automation equipment such as
programmable logic controllers (PLCs), heating, vacuum and air conditioning (HVAC)
equipment, fire suppression systems, utility connections, etc. are housed.

The cleanrooms are built entirely at a vendor’s manufacturing site. At the close of the
manufacturing process, they are factory tested. After this testing, they are shipped and moved
into the ultimate host facility. Due to the utility infrastructure within the cleanrooms, connections
to the host facility are minimal, and infrastructure within the host facility is also minimal. High
level advantages include being able to build the modules rapidly without the need for special
permits, the lack of required infrastructure at the ultimate destination, the ability to move and
repurpose the cleanrooms, and depreciating the cleanrooms on an accelerated basis as process
equipment, as opposed to the traditional facility timeframe (6).
Engineering expertise is required both for the cleanroom and the outer structure. Compared with
the fairly standard cleanroom approach in most cases, however, there is less to engineer using
this approach.

A leading architecture and engineering firm considered the amount of time required to build a
2000L monoclonal antibody (mAb) facility. The study considered three types of facility options:
traditional, modular wall panel, and prefabricated cleanrooms.

Figure 1 presents findings.

Figure 1: Timelines for different types of plant construction project

[all figures courtesy of the authors].

As can be seen in Figure 1, the time differences among the three models are substantial, with
prefabricated systems being much faster. For one manufacturer, using the prefabricated approach
allowed the facility to be ready for operation 16 months after the start date (1) compared with 25
months for the paneled approach and 27 months for the stick-built approach. Construction of the
prefabricated system solution was faster due, in part, to the fact that the cleanrooms were built in
parallel with the building or refurbishment of the host facility (Figure 2). Such an approach is
not possible with the other construction options, because the structures must be constructed after
the host facility is substantially complete.

Figure 2: A prefabricated cleanroom POD, containing controls and utilities.

An additional factor that also saves time, which this study did not consider, is the fact that
prefabricated cleanrooms use standard designs. Instead of creating new designs from scratch,
these standard designs can be used to reduce the design time and cost effort.

As noted, some standardization of cleanroom options can reduce the time required to build out a
facility, using a prefabricated approach. But could standardization also lead to other advances as
it has in other industries, enhancing speed to market without sacrificing quality or utility?

Procter and Gamble showcased an example of what might be possible for pharma at the
International Society for Pharmaceutical Engineers’ (ISPE’s) 2014 Annual Meeting. The
presentation discussed the use of standardized shell buildings that could be erected in
weeks. Parallel to the construction of the building shell, prefabricated manufacturing
modules were
Reducing Cleanroom Complexities and Cost
Why shouldn’t biopharmaceutical manufacturers be able to leverage standardized construction
practices to improve time to market?
Aug 01, 2018
By Sidney Backstrom, Maik W. Jornitz
Pharmaceutical Technology
Volume 2018 Supplement, Issue 3, pg s26–s28

Mixing and matching, in synch with demand

The prefabricated manufacturing modules were standardized and could be mixed and matched
into the shell building. Depending on demand, they could also be exchanged, in case regional
demand for one product rose or fell. Standardizing the system created budget and timeline
robustness, as well as scaling effects to reduce costs (7).

Another example comes from the automotive industry. In automobile manufacturing today, the
core product is standardized, but also configurable, with options that are related to aesthetics or
performance. Standardizing the core product keeps costs low and delivery times short, and
adding options to that core does not increase either factor significantly.

If carmakers sought to design each vehicle anew, with no standard platform in place, costs would
be astronomical and the efficiency of production and delivery would be exceedingly low. The
question is: Can the biopharmaceutical industry mirror these two examples, especially in the cell
and gene therapy space? Why shouldn’t it be possible to standardize these processes, unit
operations, and surrounding cleanroom infrastructures all the way to the facility platform?

Standardization vs. status quo

Why has such standardization been achieved, or even become the norm, in other industries but
not the biotech industry? Is it because the engineering or processing needs are that much more
sophisticated than other industries, or is it because the supplier infrastructure in the biotech
industry prefers self-preservation to innovation?

More to the point, couldn’t a prefabricated, standardized but configurable cleanroom

infrastructure solution be provided much like a car, bioreactor, or filler? Shouldn’t such
infrastructures be available from a catalogue where they can be chosen for delivery? And is there
any reason why that cleanroom couldn’t be delivered in 48 hours?

Amazon and FedEx deliver hundreds of thousands of items in two days. Mobile homes can be
ordered. Contractors build and sell “spec” houses every day. So why can’t biotech companies
choose from available options instead of re-inventing the wheel every time they have to build a
new manufacturing facility?

The goal for the industry should be to configure a cleanroom on-line or at a showroom and get it
delivered consistently with the same quality at a fixed price and timeline. End-users who adopt
this standardization approach will gain desired speed, with tremendous flexibility and greatly
reduced costs. That can only be good for the industry and, ultimately, for the patients it serves.

References

1. H.L. Levine, et al., “Efficient, Flexible Facilities for the 21st

Century,” BioprocessInternational.com, 2012.
2. J. Markarian, “Continuous Solid-Dosage Manufacturing Platform Nears Prototype
Installation,” Pharmtech.com, November 2, 2014.
3. P. Thomas, pharmamanufacturing.com, January 10,
2012, www.pharmamanufacturing.com/articles/2012/008/.
4. A. Pralong”Biopharma Asia Magazine, 2 (1), pp.12-14 (2013).
5. P. Almhem, “Modular/Flexible Facilities,” Pharmaceutical Processing, July/August, pp. 28-
30 (2014).
6. M.W. Jornitz, “Podified Manufacturing Facilities and Risk Mitigation of Aging
Pharmaceutical Facilities,” April 2014, pharmaceuticalonline.com.
7. Press Release, pharmaceuticalonline.com, September 27, 2013.

Article Details

Pharmaceutical Technology
Supplement: Outsourcing Resources
Vol. 42
August 2018
Pages: s26–s28

Citation

When referring to this article, please cite it as S. Backstrom and M. Jornitz, " Reducing
Cleanroom Complexities and Cost," Pharmaceutical Technology Outsourcing
Resources Supplement (August 2018).

About the Authors

Sidney Backstrom is vice president of business development (sbackstrom@gconbio.com), and

Maik Jornitz is president and CEO, G-CON Manufacturing, Inc.

assembled and then added into the shell when it had been completed.
 2. Selecting Primary Packaging for Parenterals
Traditional glass and polymeric materials compete for market share.
Jul 02, 2018
By Hallie Forcinio
Pharmaceutical Technology
Volume 42, Issue 7, pg 46–50

OOH/SHUTTERSTOCK.COMDespite the proliferation of new drug delivery systems for

parenteral products, glass vials remain the most widely used primary containers worldwide. This
trend is expected to continue for several years, with global demand for glass vials projected to
rise to $5.7 billion in 2024 (1).

In fact, borosilicate glass has been the primary packaging choice for parenteral products since its
development more than 100 years ago due to its excellent barrier properties, chemical resistance,
regulatory acceptance, and broad range of applications served.

But glass is not the only choice, especially for sensitive biotech products, and polymeric
materials have captured market share in recent years. Polymeric materials offer light weight,
shatter resistance, greater formability, tighter tolerances, strong barrier, and chemical
compatibility. As a result, plastic packaging is gaining ground with global demand for plastic
parenteral vials forecast to grow 7.7% per year to more than $1.6 billion(13.1 billion units) in
2021 (2).

One popular polymeric option, cyclic olefin copolymer (COC), combines formability, break
resistance, and light weight with a glass-like transparency. Other polymers such as cyclo-olefin
polymer (COP) and polyethylene naphthalate (PEN) offer similar attributes.

“The physical stability as well as the diverse design options make COC an attractive alternative
for some drugs,” explains Tom Van Ginneken, global product manager SCHOTT TopPac at
SCHOTT Pharmaceutical Systems, a supplier of glass and plastic packaging for parenteral
products. Anna Malori, business development manager at Bormioli Pharma, a producer of
pharmaceutical primary packaging both in glass and plastic, agrees and predicts, “Some fields of
application for COC will be highly sensitive drugs, biotech drugs and vaccines, and high-value
drugs such as oncology treatments.”

Glass or plastic?

With glass and polymers offering advantages and limitations in different scenarios, many factors
must be considered to determine the better choice. Some pros and cons are listed in Table I.
Commercializing new primary packaging for parenteral products tends to be time-consuming
due to the complex regulatory approval procedures that must be followed to adopt a new
packaging material. “The regulatory approval process can take years, and that is why each single
change in the glass vial configuration may be seen as an obstacle toward the final drug product
approval,” explains Malori.

As a result, many producers of glass packaging for parenteral products are leaving glass
chemistry unchanged, but they are fine-tuning processes and quality control practices and
increasing inspection capabilities to ensure shipment of flawless finished containers.

Malori says: “Each packaging choice should be strictly related to the specific needs and
characteristics of the formulation that will be contained inside.” Working in close collaboration,
the packaging supplier and drug maker identify the best packaging material and container-
closure system for the formulation. Once that decision is finalized, suppliers provide support
during the validation process.

Ginneken details the holistic approach: “We consider what we call the three Ps—product,
process, and patient. For example, we examine specific requirements for the drug. Does it need a
particularly inert packaging? We also look at the process requirements to consider how the
product will be integrated into existing manufacturing lines or how to create a low-waste filling
process, among others. Lastly, we focus on the patient as we aim to continuously meet the
patient’s comfort and needs. Therefore, we study if drug delivery in a home setting is required. If
so, the primary packaging must be easy to handle for the patient and work with self-
administration devices.”
Selecting Primary Packaging for Parenterals
Traditional glass and polymeric materials compete for market share.
Jul 02, 2018
By Hallie Forcinio
Pharmaceutical Technology
Volume 42, Issue 7, pg 46–50

Expanding applications

The need for stability and design flexibility have increased market share for polymeric materials,
especially in the prefilled syringe segments. Applications include a variety of therapeutic areas
within clinical settings, home care, or hospital-care environment.

“Benefits such as break resistance and reduced risk of syringe clogging make prefillable polymer
syringes ideal for emergency drugs and diluents,” says Ginneken. “Moreover,” he adds,
“polymer syringes are also suitable for highly viscous drugs, such as hyaluronic acid, which is
used in the cosmetic field. In addition, large-format polymer syringes of 10, 20, or 50 mL are
especially suited for infusion therapy in conjunction with syringe pumps, which allow
continuous administration of a drug, such as anesthetics or cardiovascular medications, for a
longer period of time. To ensure a seamless integration of the syringe and pump, packaging
suppliers and device manufacturers must work closely together.”

The more complex molecular structure of biotech drugs requires packaging with properties that
ensure stability. SCHOTT offers polymer as well as glass containers for the pharmaceutical
market. Polymeric packaging can offer a lower extractables and leachables profile as well as
tighter dimensional tolerances. As a result, polymeric primary packaging, such as the SCHOTT
TopPac SD COC syringe, is gaining ground for highly sensitive products.

Optimized glass containers, however, also address the need for stability. A new option for glass
containers, Valor Glass from Corning, is a coated aluminosilicate glass that became
commercially available in 2017. Eliminating boron from the formula and altering the ratios of
other ingredients results in glass with a high degree of chemical durability and surface
homogeneity and virtually eliminates delamination problems. An ion-exchange process helps
minimize breakage, cracks, and particulate contamination, while the coating lowers coefficient of
friction and eliminates cosmetic flaws. Despite the difference in chemistry, Valor Glass meets
the current United States Pharmacopeia (USP) Type I hydrolytic criteria and has low extractable
concentrations (3).

Another optimized glass option, Gx Elite Type I borosilicate glass vials from Gerresheimer,
relies on proprietary technology to produce an extremely durable, delamination-resistant vial that
is free of cosmetic defects. Compression and side-wall impact tests show the Gx Elite vials are
substantially stronger than standard Type I glass vials (4).

Gerresheimer also supplies polymeric vials. Its Gx MultiShell vial features a multilayer COP and
nylon structure, which offers clarity, shatter resistance, and barrier protection. Sizes include 2-,
5-, 10-, 15-, 50-, and 100-mL vials, which can be supplied ready-to-use (including validated
gamma sterilization). Gerresheimer also offers monolayer COP packaging for parenterals (5).

A press-blow process gives Clareo Type 2 glass vials a more uniform wall distribution, flatter
bottoms, and enhanced strength. “The vials perform better with less breakage and uniform heat
transfer,” reports Kevin McClean, quality and technical manager, Americas for SGD Pharma
Packaging. The Type 2 glass containers cost less than Type I and are an acceptable alternative to
regulatory authorities for some molecules. Clareo vials currently may be ordered in 20-, 50-, and
100-mL sizes (6).

Syringes also feature optimized glass. To maximize the quality of Ompi Nexa syringes from
Stevanato Group, the production process eliminates glass-to-glass contact and minimizes glass-
to-metal contact. Automated inspection checks each container. Options include a 1-mL long
design and a 2.25-mL design with staked needle (7).

Whether glass or plastic, the highest levels of activity are being observed in the development of
cartridges for pen and infusion pump systems and a transition from vials to prefilled syringes. In
addition, “There’s a lot of activity in auto-injectors for insulin,” says Dave Dugan, account
manager for Stevenato Group’s Ompi of America.

One of the major forces driving interest in auto-injectors is the growth in home care. Self-
administration “lessens the burden on the healthcare system,” says Uzzo Calderaro, business
development manager at Duoject Medical Systems. “When a patient can stay at home, there’s
cost savings and a better quality of life for the patient,” he explained. Well-designed auto
injectors also reduce the chance of sharps injuries, prevent loss of product, and deliver accurate
doses

Selecting Primary Packaging for Parenterals

Traditional glass and polymeric materials compete for market share.
Jul 02, 2018
By Hallie Forcinio
Pharmaceutical Technology
Volume 42, Issue 7, pg 46–50

With auto-injectors, easy, consistent operation is essential, because the devices are intended for
patient use. Uniform silicone levels are needed to ensure consistent movement of the plunger and
help keep injection duration at no more than 10 seconds. These features do not come without
challenges. “When injection time needs to be reduced, the drug needs to be concentrated, which
increases its viscosity, necessitating more pressure on the syringe and increasing the chances of
breakage,” says Dr. Nicolas Eon, SCHOTT’s global product manager, syriQ.

Made of highly inert FIOLAX borosilicate glass, the recently launched syriQ BioPure staked-
needle syringes offer low tungsten and adhesive residuals for a superior extractables and
leachables profile, plus accurate dimensions for optimal device compatibility. To maximize
mechanical resistance and minimize the chance of breakage, the syringes are produced under
strict cosmetic defect specifications in a process that eliminates glass-to-glass contact. A multi-
camera quality control system provides 100% inspection of the complex shape from tip to flange.
To accelerate speed to market, SCHOTT offers more than 40 validated configurations combining
different flange designs, 27-g or 29-g needles, and elastomer components along with full
documentation. “The availability of full documentation reduces the risk profile for the drug
maker and ensures the syringe and device work together,” notes Eon.

Some auto-injectors, especially those integrated into wearable devices, rely on cartridges.
“Cartridges occupy less space and cost less than prefilled syringes,” explains Duoject’s
Calderaro. Duoject has developed a multi-dose auto injector with a diluent-filled cartridge. The
modular, integrated Penprep Evo system simplifies reconstitution and ensures dose accuracy via
patented vacuum transfer technology, which also minimizes drug hold-up in the vial and air
transfer back to the cartridge. Configurations include 13- or 20-mm drug vials with various
diluent fill volumes (8).

Another recent auto-injector development, the SelfDose patient-controlled injector from West
Pharmaceutical Services, departs from the traditional spring-loaded design and is larger than
most pen systems. “The SelfDose injector restores control to the user, particularly for the
arthritic population who may find standard injectors difficult to use,” reports Carl Dabruzzi,
director, Self-Injection Systems at West Pharmaceutical Services. The golf-ball size top of the
larger-than-usual injector features a 1-mL long syringe. To use, the patient simply removes the
cover and pushes down to dispense. Injection speed is user controlled and may even be paused.
A visual indicator ensures proper administration. Needle depth can be customized to optimize
drug absorption, and the needle is not visible before or after injection (9).

For wearable devices, West Pharmaceutical Services offers its SmartDose drug delivery
platform. “We’re seeing a lot of IV [intravenous] products being developed for subcutaneous
administration via wearable devices,” explains Dabruzzi. Driving forces for the transition include
cost containment and patient convenience. A wearable device, he notes, reduces the need for
trips to an infusion clinic. “With one or more visits per week at $300 to $1200 [260–1030 Euros]
per visit, costs for infusions can easily add up to thousands of [US] dollars per year, plus the cost
of the drug product. Instead, the wearable device is applied and activated, and audible and visual
indicators guide the patient through the administration process.”

The SmartDose drug delivery system is based on a user-loaded, custom COP cartridge with
septum/cap and FluroTec piston. Pre-programmed delivery times and duration can give the
patient a more comfortable injection experience, particularly when delivering high-volume or
high-viscosity drugs (10). Dabruzzi adds, “A patient who experiences pain or feels intimidated
about self-injection is less likely to be compliant. So increased patient comfort is likely to
improve patient compliance, which leads to better outcomes.”

References

1. Freedonia, “World Pharmaceutical Packaging Industry Study #3269,” July 2015, p. 73-75.
2. Freedonia, “World Pharmaceutical Packaging Industry Study #3591,” January 2018, p. 66-67.
3. H. Forcinio, Pharm. Tech. Europe 29 (9) 18-19 (2017).
4. Gerresheimer, “Gx Elite Glass Vials Setting New Standards Regarding Quality
Requirements,” www.gerresheimer.com/en/services/innovations/elite-glass-vials.html, accessed
May 24, 2018.
5. Gerresheimer, “Gerresheimer to Unveil Innovative Vials Made from Glass and Plastic at the
PDA in Orlando,” Press Release, March 15, 2018.
6. SGD Pharma Packaging, “SGD Pharma Introduces Its New Clareo Range,” www.sgd-
pharma.com/company-news/sgd-pharma-introduces-its-new-clareo-range, accessed May 24,
2018.
7. Stevenato Group, “Prefillable Syringes,” https://pharma.stevanatogroup.com/glass-primary-
packaging/products-platf..., accessed May 24, 2018.
8. Duoject Medical Systems, “Penprep EVO,” http://duoject.com/realisations/penprepevo/,
accessed May 24, 2018.
9. West Pharmaceutical Services, “SelfDose Patient-Controlled Injector,”
www.westpharma.com/products/self-injection-platforms/selfdose, accessed May 24, 2018.
10. West Pharmaceutical Services, “SmartDose Gen. I 3.5 mL Drug Delivery Platform,”
www.westpharma.com/en/products/self-injection-platforms/smartdose/smartd..., accessed, May
24, 2018.

Article Details

Pharmaceutical Technology
Vol. 42, No. 7
June 2018
Pages: 46–50

Citation

When referring to this article, please cite it as H. Forcinio, "Selecting Primary Packaging for
Parenterals," Pharmaceutical Technology 42 (7) 2018.

About the Author

Hallie Forcinio is Pharmaceutical Technology’s Packaging editor, editorhal@cs.com.

3. Sterility Test Isolators for Aseptic and Toxic Drug

Products are Ergonomically Designed
May 24, 2018
By Pharmaceutical Technology Editors

Source: Metall+Plastic, a subsidiary of

OptimaProduct safety is the focal point during the filling of pharmaceutical products. Sterility
test isolators are used to check the purity and sterility of filled batches and to increase safety.
New sterility test isolators from Metall+Plastic, a subsidiary of Optima, were designed as plug &
play isolators for aseptic (STISO) and aseptic-toxic (STISOtox) applications.

The sterility test isolators are easy to adjust to customer requirements due to their modular
design. The standard version includes four glove ports in the isolator chamber, but it is also
available with two or three glove ports. The material transfer chamber (MTC) can be installed to
the left or the right of the chamber or on both sides. The MTC can also be retrofitted at a later
date. It comes in two different sizes in the standard version. The STISO can be operated from
one side and, therefore, is suitable for space saving installation against the wall, allowing the
STISO to be used for small batches. Additional options that can be included are: particle
monitoring, air sampler, sterility test pumps, and scales.

The results of an ergonomic study were incorporated into the design of the STISO: the operator
panel is at an optimal height, and it is pivotable and angle adjustable. In addition, the machine
allows for sufficient legroom. The insertion heights can be adjusted to match the operator’s
height. It is also possible to work in a sitting position with an ergonomically designed pivoting
chair. Operators also benefit from the loading cart and trolley. The STISO glove testing units are
integrated on the side of the housing to make the operation easy.

While processing toxic substances for live vaccines, viruses, and bacteria, it is crucial to
guarantee the operator’s and the product’s safety. HPT filters from Metall+Plastic separate the
airborne particles from the product and can handle a volume flow of approximately 1300 cubic
meters per hour. The filters offer the opportunity to perform an integrated filter integrity test, and
the plastic housing can be burned without any residue.

The unit offers short cycle times using catalytical ventilation to ensure that the hydrogen
peroxide used for the isolator decontamination is removed quickly. The STISO uses
maintenance-friendly flash evaporation. With the patented DECOjet process from
Metall+Plastic, the liquid hydrogen peroxide is transformed into a gaseous state. The
advantage

4. Identifying TPPs and CQAs for a Lyophilized

Parenteral Product
Quality by design highlights product and process understanding and control, integrating quality
risk management, and is also considered a quality system for managing a product’s lifecycle.
Jun 02, 2018
By Denise L. Miller, Carrie A. Shults, Edward H. Trappler
Pharmaceutical Technology

Volume 42, Issue 6, pg 38–41

powerphotos/shutterstock.comTarget product profiles (TPPs), also referred to as quality target

product profiles (QTPPs), are a summary of the proposed design attributes and characteristics of
a finished drug product. TPPs are useful tools that assist in the fundamental principles of quality
by design (QbD). TPPs are dynamic; they provide an initial introduction to the anticipated
attributes inproduct design, to be further redefined as new knowledge is gained over the product
lifecycle. As a method providing further focus on product attributes and to aid in the
development process, potential critical quality attributes (CQAs) can be derived from the TPPs.
As stated in the Guidance for Industry, Q8 (R2) Pharmaceutical Development, “CQAs are
physical, chemical, biological, and microbiological properties or characteristics that should be
within a certain specified range to ensure finished product quality” (1).
Throughout pharmaceutical development, the focus remains on establishing the CQAs. Initially
identifying the desirable and essential CQAs, these and additional potential CQAs are modified
and refined as knowledge increases through the development pathway. Many, if not all, of the
developed CQAs become the basis of the final TPP. Essential CQAs become the final product
release specifications (See Figure 1). The TPPs and CQAs result from enhanced product
knowledge and, as such, aid in discussions with drug discovery, product development teams,
clinical groups, manufacturing groups, as well as regulatory authorities. This knowledge allows
for the further pursuit of improvements through QbD and risk-based decisions, along with
product and process improvements. Per Q8, “Such a systematic approach can enhance the
process to achieve quality and help regulators to better understand a company’s strategy.

Figure 1: The progression through the steps in establishing finished product specifications based
on essential and desired critical quality attributes (CQAs) from defined target product profiles
(TPPs). It is meant as a starting point, to bring focus to establishing TPPs early in development,
and will be unique for each product [figure courtesy of the authors].

Product and process understanding can be updated with the knowledge gained over the product
lifecycle. A greater understanding of the product and its manufacturing process can create a basis
for flexible regulatory approaches” (1).

QbD has been the industry focus because it offers the benefits of gaining greater product and
process knowledge and understanding to all vested pharmaceutical development, manufacturing,
quality, and regulatory groups. Knowledge-based decisions offer improved processes through
systematic approaches and continuous improvement. Some of the benefits of a greater product
and process understanding are greater product value, efficient and effective control programs,
flexible regulatory approaches, fewer batch failures, and in the end, a greater return on
investment and profitability.

Other benefits a company could realize are a decrease in post-approval submissions, proficient
technology transfer to manufacturing, enhanced regulator confidence of robust processes, which
result in reduced time to market, improved yields, lower cost, fewer investigations, increased
drug availability, fewer recalls, and most importantly, consumer confidence (See Table I). QbD
allows for first-time-right and lean assets management by using the risk perceptions. Thorough,
proactive, and beneficial QbD begins with properly identifying TPPs.

Identifying TPPs

From drug discovery, prior to and during development, TPPs are identified based on perceived
attributes of the finished product. TPPs should be reexamined as new information and data
become available. The basis for TPPs and resulting CQAs should be those that ensure a product
is suitable for its intended use. For lyophilized parenteral products design, there are unique
therapeutic regimens, inherent product requirements, and manufacturability of processing
methods that are important to consider for product design criteria. Some of the aspects that need
to be addressed are as follows.

Therapeutic regimen. Consider the frequency of administration. Is a multi-dose vial

appropriate? The course of therapy should be addressed. Over what time period is this given?
Does the product have adequate stability to support hold time in the constituted state?

The route of administration should also be considered. Will it be given intra-muscular (IM),
subcutaneous (SubQ), intravenous (IV), peripherally inserted central catheter (PICC), or central
line? What is required for the route of administration? What is the appropriate pH or isotonicity?
What are the maximum volume allotments? For example, higher concentrations of citrate buffer
can cause irritation at the injection site; tonicity and a high volume SubQ can cause pain or
irritation at the site. Also consider if the therapy is or can be co-administered. Will there be
compatibility with the equipment required such as needles or tubing?

Patient population and end user. Characteristics of the patient population should be
determined. Is this a pediatric, adult, or geriatric patient? Are there excipient considerations for
this population such as limiting L-Arginine use in pediatrics or sugar content for people with
diabetes. For example, there are preferred excipients for lyophilized products.

Consider the disease state or health conditions of the patients. Are the patients immuno-
compromised? Are there contraindications for excipients?
The type of end user should also be taken into consideration. Is the product to be used by the
patient at home and/or be self-administered, if so, is the device capable of being self-injected? Is
the end user a hospital, clinic, or IV therapy parlor? If administered in a pharmacy setting, is a
multi-dose vial preferred? Will the product be used for emergency medicine, such as EMT,
military, or remote environment? Will it require quick reconstitution and injection? Also, is end-
user compliance required and are steps limited for ease of use?

Inherent product requirements. The following product requirements should be considered:

• Chemical/biochemical stabilization

• Hydrolysis

• Deamidation

• Decarboxylation

• Physical stabilization

• Polymerization

• Aggregation

• Protective agents

• Light

• Oxygen

• Heavy metals

• Stability under various conditions

• Bulk solution

• Dried product for storage

• Constituted solution.

Manufacturability of processing methods. The following processing methods should be

considered:

• Bulk solution characteristics

• Solution sensitivities
• Fill volume

• Stability profile.

Identifying CQAs

CQAs are identified by quality risk management and experimentation to determine the effect of
variation on product quality. Initial CQAs are refined as knowledge increases through the
development pathway. Once identified, CQAs then need to be prioritized as essential or desirable
through risk-based analysis to form a hierarchy of relative importance. Through pharmaceutical
development and with a clinical-use perspective, the focus needs to remain on the essential
CQAs. As the drug presentation progresses through pre-clinical development, laboratory and
pre-clinical studies yield further insight into the achievable CQAs. These studies, as well as
subsequent human clinical studies, aid in identifying CQAs as essential versus desirable, and the
product knowledge base becomes greater. Drug product design warrants continued assessment
and development of essential CQAs before the product moves from pre-clinical development and
first-in-human clinical studies to Phase II clinical studies, and ultimately, commercialization.

Typical CQAs for solid dosage forms are aspects affecting purity, strength, stability, and
bioavailability. For in-process controls and CQAs of lyophilized parenteral products, purity of
the bulk solution when dealing with assay or absence of degradation could be defined by a
product’s storage conditions or time. Another aspect of in-process bulk solution purity is
microbiological and endotoxin, which limits are discussed within the United States
Pharmacopeia(USP) <61>, Microbiological Examination of Nonsterile Products, USP <71>
Sterility Testing, and USP <85> Bacterial Endotoxins Test (2, 3, 4). Strength needs to be
considered as well as stability. CQAs specific to parenteral products include microbial aspects of
sterility and endotoxin, physical properties of a parenteral product including both intrinsic and
extrinsic particulates, chemical or biochemical aspects of assay and purity, as well as attributes
of a lyophilized product of complete dissolution. Reconstitution time for complete dissolution of
the dried product is also considered a CQA. The criticality of the reconstitution time may,
however, be different and dictated by the clinical use aspects. For example, the reconstitution
time for a product on an ER “crash cart” may be more critical than an antibiotic for prophylactic
pre-surgery, reconstituted in a hospital pharmacy for administration the next day.

Stability entails conditions as a bulk solution, in the dried state during storage, as well as the
constituted finished product. The ability to handle temperature excursions during storage is also
important. In comparison, lyophilized products have different CQAs than ready-to-use
parenterals. These additional finished product attributes are either direct or contributory. They
include reconstitution time and volume and finished product testing in both the dried and
constituted state. As an example, the product needs stability data and assay; these would be
direct. However, they would be impacted by residual moisture, which would be contributory.

CQAs direct product in process and final product release specifications (See Table
II). Specifically, for lyophilized parenteral products, reconstitution with a proper diluent and
storage of the constituted solution can be extremely important if the product degrades quickly
upon reconstitution. In any case, there needs to be an evaluation and an expiry for the product in
a constituted state. As noted earlier, there may also be conditions that require a quick
reconstitution such as a product on an emergency “crash cart.” As well, the product presentation,
such as products in cartridges and syringes for a self-administered product, reconstitution time
becomes paramount. Additional considerations should include excipient selection, excipient
interactions, and container closure selection, to name a few.

Final commercial product profiles are instituted by the CQAs that direct targeted in-process
assessments and final product release specifications. Assessing quality aspects for in-process
measurements may utilize basic methods such as solution clarity, pH, and simple analytics such
as UV/Vis for verifying concentration. Verifying the quality attributes of finish product entails a
greater number of assessments using more sophisticated and both qualitative and quantitative
methods. These can span simple tests such as pH, simple weights and measures such as content
uniformity and deliverable volume, and dissolution, to higher level analytical methods such as
sub-visible particles and stability indicating chemical and biochemical assays. In addition, sterile
parenteral products, including those lyophilized, need to demonstrate they are free of
microorganisms and have established endotoxin limits (5).

CQAs also need to be assessed and verified during the approved storage duration, up to and
including the products expiry date. These specifications encompass all the same product
attributes at the time of the batch release, including the absence of degradation products. It is
also imperative to include not only the assay and purity upon initial reconstitution but also after
the allowed storage interval for the constituted solution.

Manufacturing considerations

However, it is not only the physical product end-result that should be considered when reviewing
TPPs and CQAs. Manufacturability considerations are paramount when a product progresses
through design and development, to clinical, and ultimately commercial manufacturing. These
considerations encompass processing time and compatibility of materials and the process
capability within the intended manufacturing operation. Container closure selection also
continues to be a focus, as batch size and yield in manufacturing, and space for distribution and
storage at the final destination, are influenced by the packaging selected (6).

As product and process knowledge are gained and added into the dynamic TPP, the wealth of
knowledge becomes a source of effective communication for technology transfer. The data can
also be utilized in decision making, risk assessment, communications with FDA and sponsors,
and in process validation. It lends to continual process improvements and control strategies as
the product evolves to realization. It is an effective tool to streamline activities and manage risks
starting with the end goal in mind.

Conclusion

In summary, establishing CQAs from TPPs for quality attributes of a parenteral product is an
ongoing process that should originate during development and follow throughout the product
lifecycle. This is an essential application of QbD principles and parallels those reflected in Q8
(R2) (1). This ever-evolving profile, when started early on in development with intended product
attributes in focus, allows for increased understanding, communication, and quality. Among the
benefits are a clear direction during development, improved processes, increased regulatory
flexibility, and cost reduction. The result is a greater level of assurance that a product is suitable
for its intended use and meets the needs and expectations of the end user.

References

1. FDA, Guidance for Industry: Q8 (R2) Pharmaceutical Development(Rockville, MD,

November 2009).
2. USP, USP40-NF 35 General Chapter <61>, “Microbiological Examination of Nonsterile
Products: Microbial Enumeration Tests,” USP–NF 117-123.
3. USP, USP40-NF 35 General Chapter <71>, “Sterility Testing,” USP–NF136-143.
4. USP, USP 40-NF 35 General Chapter <85>, “Bacterial Endotoxins Test,” USP–NF163-169.
5. L. Daukas and E. H. Trappler, Pharmaceutical & Cosmetic Quality, 2, 5, 21-25 (1998).
6. M. J. Akers and J. Michael, “Sterile Product Packaging Systems” in Sterile Drug Products:
Formulation, Packaging, Manufacturing, and Quality, J. Swarbrick, Ed. (Informa Healthcare
Inc., New York, NY, 2010), pp. 29-47.

Article Details

Pharmaceutical Technology
Vol. 42, No. 6
June 2018
Pages: 38–41

Citation
When referring to this article, please cite it as D. L. Miller, C. A. Shults, and E. H. Trappler,
"Identifying TPPs and CQAs for a Lyophilized Parenteral Product," Pharmaceutical
Technology 42 (6) 2018.

About the Authors

Denise L. Miller is document control specialist; Carrie A. Shults is associate director,

Development Sciences; and Edward H. Trappler is president—all at Lyophilization
Technology, Inc.

is that little maintenance work is needed in the evaporator area.

Source: Optima