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Establishing cGMP Manufacturing Capability
for Phase 1 Sterile, Dispersed, Injectable
Dosage Forms
Donald Pennino, Ph.D, VP, QA/ARD &
Jingjun Huang, Ph.D., CEO
Ascendia Pharmaceuticals LLC
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
1. Introduction
As a product transitions from pre-clinical development to
a clinical development phase, the manufacturing process
takes on a much greater role in the overall success of the
project. This transition is particularly difficult for emerging
pharmaceutical companies whose expertise typically lies in
the biology and chemistry of how their drug interacts with
targets in the body, and less on the engineering, regulatory
and quality aspects of manufacturing the drug product. This
critical milestone is made even more challenging when the
drug product is intended to be a sterile, injectable dosage
form as the manufacturing and quality requirements can
be overwhelming for a small company. Most small pharma
companies turn to Contract Development and Manufacturing
Organizations (CDMOs) to outsource this activity, as the cost
to establish the capability internally often does not merit
the investment for an early-stage product.
Many CDMOs do not provide manufacturing services for
injectable products, and those that do often have facilities
suitable for large scale production. Since early-stage
products are almost always manufactured in small batches,
there is a market need for CDMOs with the flexibility to
provide manufacturing services for Phase I sterile dosage
forms. For example, in some cases, it may be advantageous
for a CDMO to establish a GMP area within a “laboratory
setting” for the manufacture of drug product in early
development. The rationale for this approach is to avoid the
significant investment in setting up a dedicated facility and
to create simpler, more flexible systems that meet GMP
requirements, but are tailored for the specific activity
envisioned. As long as the appropriate GMP controls
are maintained, especially as related to operator safety,
cleaning, and prevention of cross-contamination, there is
no compliance barrier to using “lab-type” facilities for the
manufacture of early phase clinical batches. This article
describes the considerations for establishing this capability,
and focuses on dosage forms that are sterile and dispersible.
Page 2
Production of the
first clinical trial
materials for a
new pharmaceutical
dosage form is a
significant milestone
event in the
development of
a pharmaceutical
product.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage FormsEstablishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
2. Regulatory Landscape for Phase 1 Dosage Forms
On September 15, 2008 the FDA made effective an
amended rule that applies to small-molecule drugs and
biologics, including vaccines and gene therapy products.
The note in the Federal Register of 15 July 2008 (Volume
73, No. 136) announced an adaptation of 21 CFR 210 and 211:
investigational medicinal products solely intended for use
in Phase 1 are to be exempted from complying with the
“final rule” under FD&C Act 505(i) (21 U.S.C 355(i)). The
text stresses that the cGMP requirements of 21 CFR 211
are applicable only to Phase 2 and Phase 3 drugs (note,
however, the exemption does not apply once the
investigational drug has been made available for use by
or for the sponsor in a Phase 2, a Phase 3 trial, or if the
drug has been lawfully marketed).
“FDA’s position is that the United States’ [GMP]
regulations were written primarily to address commercial
manufacturing and do not consider the differences
between early clinical supply manufacture and
commercial manufacture,” the agency says.
For example, the requirements for a fully validated
manufacturing process, rotation of stock for drug product
containers, repackaging and relabeling of drugs and
separate packaging and production areas need not apply
to investigational drug products made for use in Phase 1
trials, the agency says. This makes for solid rationale, as
the typical batch size needed for Phase 1 clinical trials is
typically much smaller in comparison to Phase 3 and
commercial scale batches, and hence the critical controls
needed for Phase I should focus on safety of manufacture
rather than qualification of processes at this point of drug
development (note, however, the FDA did emphasize the
importance of meeting the “statutory GMP requirements”
of the Food and Drug Act ” 501 (a)2(B) which direct 21 CFR
Parts 210 and 211).
Page 3
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
In connection with the final rule on Phase I drug GMPs, the
FDA issued a guidance recommending approaches to satisfy
statutory GMP requirements for such drugs:
“During product development, the quality and safety of
Phase I investigational drugs are maintained, in part, by
having appropriate [quality control (QC)] procedures in
effect,” the guidance states. “Using established or
standardized QC procedures and following appropriate
cGMP will also facilitate the manufacture of equivalent or
comparable IND product for future clinical trials as needed.”
While the basic requirements to reduce or eliminate
contamination that would cause adulteration in
non-sterile drug products are demanding, the standards
for aseptic manufacturing of medicinal drug products are
even more stringent. The pharmaceutical product must be
non-pyrogenic, in addition to a strict sterility requirement.
Medicinal drug products that do not meet the sterility and
non-pyrogenicity requirements can otherwise cause severe
harm or a life-threatening health risk to the patient. Hence,
these attributes are of utmost importance and concern
during Phase 1 manufacture. Since the injectable dosage
form must be sterile, the drug product can be terminally
sterilized in its packaging, or manufactured aseptically.
Aseptic Manufacturing RegulationsIn Europe, aseptic manufacturing of sterile products is still
seen as a last resort which is only acceptable if all methods
of terminal sterilization in the final sealed container have
be excluded. Such being not feasible or applicable, for
example when the drug substance is thermally labile, the
EU guidelines require the sterilization in the final container
closure system whenever possible. Only the stability of the
drug substance is considered, but not the container closure
system. The European Pharmacopoeia (EP) prioritizes the
terminal sterilization of the final container in manufacturing
sterile drug products. The “EU Guidelines to GMP for
Medicinal Products for Human and Veterinary Use, Annex
1, Rev. 2008, Manufacture of Sterile Products” compiles the
recommended procedures for sterile products and includes
the aspects of aseptic manufacturing.
Page 4
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage FormsEstablishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
In the USA, the FDA’s 2004 publication “Guidance for
Industry Sterile Drug Products Produced by Aseptic
Processing” describes the expectations of the FDA for the
validation of aseptic processing in a more detailed manner.
This guidance updates the 1987 guidance primarily with
respect to personnel qualification, cleanroom design and
isolators, air supply system, integrity of container closure
systems, process design, quality control, environmental
monitoring, and review of production records. The use of
isolators for aseptic processing is also discussed. According
to the latest guidance, acceptance criteria for the
evaluation of media fill states that each contaminated unit
should be examined independent of the number of filled
units. The microbial environmental monitoring (more
frequency in testing) is accorded more importance to get
greater quality assurance. Table 1 lists an overview of
regulatory guidelines for aseptic processing.
Table 1. Overview of International Requirements, Guidelines
and Recommendations for Aseptic Manufacturing
Provided By Requirement / Guideline / Recommendation
PH. Eur, 5th ed., ch. 5.1.1, 20052
Methods of Preparation of Sterile Products
USP <1211>, 20165 Sterilization and Sterility Assurance of Compendial Articles (Manufacturing of Sterile Drug Products)
EudraLex4 EU Guidelines to GMP for Medicinal Products for Human and Veterinary Use, Annex 1, Rev 2008, Manufacture of Sterile Medicinal Products, 2003
ISO 13408-1 (2015)7
Aseptic Processing of Health Care Products Part 1: General Requirements
ISO 14644-1 (2015)8
Cleanrooms and Associated Controlled Environments. Part 1 (Specification for particles in air in clean rooms)
PIC/S (Pharm. Inspection Co-Operation Scheme)
Recommendation on the Validation of Aseptic Processes (2011)
PDA Technical Report No 13 rev. (2014) 16
Fundamentals of an Environmental Monitoring Program
PDA Technical Report No 22 rev. (2011) 14
Process Simulation Testing for Aseptically Filled Products
PDA Technical Report No 28 rev. (2006) 15
Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals
PDA Technical Report No 26 rev. (2008) 17
Sterilizing Filtration of Liquids
US FDA, CDER, revised 2004
Guidance for Industry, Sterile Drug Products Produced By Aseptic Processing. Validation with Media Fill.
USP <1116>, 201411 Microbiological Monitoring of Clean Rooms and Other Controlled Environment
Page 5
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
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3. Sterile, Dispersable Dosage Forms
SuspensionsSome drugs are insoluble in all acceptable media and
must, therefore, for parenteral use, be administered as a
suspension. One advantage is that drugs in suspension are
often chemically more stable than in solution; however, their
primary disadvantage is physical stability; i.e., that they tend
to settle over time leading to a lack of uniformity of dose.
Issues with settling can be minimized by careful formulation
and by shaking the suspension before each dose is
delivered. Physical stability in suspensions is controlled by
(1) the addition of flocculating agents to enhance particle
“dispersability” and (2) the addition of viscosity enhancers
to reduce the sedimentation rate in the flocculated
suspension. Flocculating agents are electrolytes which carry
an electrical charge opposite that of the net zeta potential
of the suspended particles. The addition of the flocculating
agent, at some critical concentration, negates the surface
charge on the suspended particles and allows the formation
of floccules, or clusters of particles, that are held loosely
together by weak van der Waals forces. Since the particles
are linked together only loosely, they will not cake and may
be easily re-dispersed by shaking the suspension. Floccules
have approximately the same size particles; therefore a
clear boundary is seen when the particles settle. Viscosity
enhancers are typically hydrocolloids (natural, semisynthetic,
or synthetic) or clays use in a concentration range from 0.5%
to 5%, but the target viscosity will depend on the suspended
particle’s tendency to settle.
A couple methods are used to prepare parenteral
suspensions. First, aseptically combining sterile powder
and vehicle involves aseptically dispersing the sterile, milled
active ingredient(s) into a sterile vehicle system (solvent plus
necessary excipients); aseptically milling the resulting
suspension as required, and aseptically filling the milled
suspension into suitable containers. For example, this
process is used for preparation of parenteral procaine
penicillin G suspension. Or, second, in-situ crystal formation
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage FormsEstablishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
Page 7
by combining sterile solutions. In this method active
ingredient(s) are solubilized in a suitable solvent system,
a sterile vehicle system or counter solvent is added that
causes the active ingredient to crystallize, the organic
solvent is aseptically removed, the resulting suspension is
aseptically milled as necessary, and then filled into suitable
containers. For example, this process is used for testosterone
and insulin parenteral suspensions.
Nano-ParticlesA drug’s low solubility often presents a serious challenge to
developing bioavailable dosage forms. This challenge can be
exacerbated for drugs with chemical stability issues when
solubility-enhancing approaches utilize excipients that
are incompatible with the drug substance. To overcome
these challenges many technologies have been developed
including particle size reduction to nanometer-size drug
crystals with greater surface area for dissolution, production
of amorphous solid dispersions for reducing the energy
required for dissolution, and lipid-based drug delivery
systems for dissolving a hydrophilic drug in either a lipid
or oil phase.
Nano-EmulsionsOil-in-water emulsions, which are comprised of oil
droplets dispersed in an aqueous continuous phase, can
provide unique solutions for overcoming drug solubility and
stability problems; for example, Diprivan® (propofol), an
injectable anesthetic, is an nano-emulsion.
Emulsions can be characterized as macro, micro or nano.
Macro-emulsions are typically opaque in appearance, since
the average particle size of the hydrophobic droplet in a
macro-emulsion is typically > 500 nm and thus scatters light.
Micro-emulsions and nano-emulsions are obtained when the
size of the droplet is typically in the range of 50-500 nm. In
addition, emulsions in this size range can appear translucent
or optically clear if the average oil droplet size is < 100 nm,
as droplets in that size range no longer scatter light.
Sterile, dispersible
dosage forms
include suspensions,
nano-particles and
nano-emulsions -
these last two
formulation options
are being increasingly
utilized due to their
ability to improve
bioavailability issues
with poorly
soluble drugs.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
The distinction between micro- and nano-emulsions
relates to their thermodynamic stability. Micro-emulsions
are thermodynamically stable due to the use of sufficient
co-solvents and co-surfactants to prevent Ostwald ripening -
essentially the coalescence of the droplets into larger
particles. Ostwald ripening is the most frequent physical
instability mechanism, although gravitational separation can
also occur with larger particles. Nano-emulsions contain
much less of the stabilizing co-solvents and co-surfactants,
and as such are meta-stable and more susceptible to
Ostwald ripening. In addition, nano-emulsions require
greater kinetic formation energy, and are usually prepared
using high-pressure homogenization or ultrasonic
generators. Because of the undesirable side-effects
caused by many solvents and surfactants, micro-emulsions
are disadvantageous compared to nano-emulsions. In
order to achieve physically stable nano-emulsions, long
chain triglyceride oils are sometimes employed, but
typically require the use of organic co-solvents or toxic
co-surfactants (e.g., Cremaphor). The addition of co-solvents
and co-surfactants significantly reduces the safety and
tolerability profile of the pharmaceutical formulation. These
excipients may not be suitable for pediatric administration,
may cause injection site pain and irritation, and are
becoming less acceptable in general for use in
pharmaceutical formulations.
Page 8
4. Facility Size & Manufacturing Space Considerations
Matching the product to an appropriate facility size is
important. Facility infrastructure typically increases along
with facility size, and facility size increases with the scale
of the pharmaceutical project. The development phase of
the drug will dictate the capacity requirements of the
formulation and fill. For larger, later stage production
activities the maximum capacity of the facility is critical to
ensure success, but this is not a critical factor for early-stage
development projects. It is important to evaluate the
product’s requirements and determine the best fit.
A “bigger is better”
philosophy is not
always true in drug
development and
processing. In early
phase trials the quantity
of the drug substance
available is often very
small. Matching the
equipment scale and
material handling
expertise with the
product is essential
in order to ensure a
successful, cost-effective
outcome.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage FormsEstablishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
Page 9
The ideal CDMO is one that can grow with a product’s
success, but this is difficult — if not impossible — to find.
Pure CMOs that manufacture high volume commercial
products typically lack the equipment and personnel to
manage a developing product that requires low volume,
and flexibility in scheduling. Companies that specialize in
small volume early stage products have staff experienced
in rapid small-scale manufacturing campaigns. A smaller
support staff generally has greater flexibility with regard to
changes and timing. The lead time for changes at a smaller
CDMO should be less than for a CMO that is use to filling lots
greater then 100,000 units per day. Although larger CMOs
have much greater capacity, they tend to be more rigid and
generally have defined systems in place that are not easily
changed. Scheduling is done well in advance (the lead time
for scheduling or bringing a product in can be six months
to a year) so the lead time for changes can be a factor.
Evaluating the structure that you require for your stage
of production is an important aspect in choosing the
CDMO that will meet your current and potential
future requirements.
5. Equipment - Both Process and Cleanroom
Cleanrooms are used in practically every industry where
small particles can adversely affect the manufacturing
process. A cleanroom is any given contained space where
provisions are made to reduce particulate contamination
and control other environmental parameters such as
temperature, humidity and pressure. The key component is
the High Efficiency Particulate Air (HEPA) filter that is used
to trap particles that are 0.3 micron and larger in size. All
of the air delivered to a cleanroom passes through HEPA
filters, and in some cases where stringent cleanliness
performance is necessary, Ultra Low Particulate Air (ULPA)
filters are used.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
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Cleanrooms are classified by how clean the air is. In Federal
Standard 209 (A to D) of the USA, the number of particles
equal to and greater than 0.5mm is measured in one cubic
foot of air, and this count is used to classify the cleanroom.
This metric nomenclature is also accepted in the most recent
209E version of the USA Standard. The newer standard
is TC 209 from the International Standards Organization
(ISO 14644-1). Large numbers like “class 100” or “class 1000”
refer to the 209E Standard; the standard also allows
interpolation, so it is possible to describe e.g. “class 2000.”
Cleanrooms classified using single digit numbers refer to
ISO 14644-1 standards, which specify the decimal logarithm
of the number of particles 0.1 µm or larger permitted per
cubic meter of air. So, for example, an ISO class 5 cleanroom
has at most 105 = 100,000 particles per m3. Both FS 209E
and ISO 14644-1 assume log-log relationships between
particle size and particle concentration. For that reason,
there is no such thing as zero particle concentration.
Ordinary room air is approximately class 1,000,000 or ISO 9.
Personnel selected to work in cleanrooms undergo extensive
training in contamination control theory. They enter and
exit the cleanroom through airlocks, air showers and/or
gowning rooms, and they must wear special clothing
designed to trap contaminants that are naturally generated
by skin and the body. Since Phase 1 batches usually are
small scale, one popular alternative of CDMOs is to utilize
compounding isolators for sterile manufacture. Isolators
consist of a decontaminated unit, supplied with class 100 or
higher air quality that provides uncompromised, continuous
isolation of its interior from the external environment (e.g.,
surrounding clean room and personnel).
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage FormsEstablishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
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An isolator is defined as an ISO 5 enclosure if it meets the
following criteria:
• uses rapid transfer ports or another type of
decontaminated, high-integrity interface to transfer
compounding materials into the isolator;
• uses an automatic sporicidal
decontamination system;
• constantly maintains a significant overpressure
relative to the surrounding environment; and
• the manufacturer provides documentation verifying
that the isolator can maintain ISO 5 at all times.
Any Compounding Aseptic Isolator (CAI) that does not meet
all of the isolator criteria would be classified as a restricted
access barrier system (RABS). A RABS is an ISO 5 enclosure
that provides a physical separation from the compounding
area through the use of glove ports, but the openings for
transferring materials would not provide the same level of
protection as an isolator. In addition, the RABS is cleaned
and decontaminated manually.
Aseptic Manufacturing ConsiderationsAseptic manufacturing consists of a lot of single working
steps. But the whole process is only as good as the worst
single step. To achieve the aim of a sterile product, several
aspects have to be considered and have to be separately
validated. In the end, process simulation with media fill is the
key validation measure and allows the final evaluation of the
appropriateness of the whole process. It is state-of-the-art
to produce medicinal products under aseptic controlled
conditions. This control requires monitoring of the
environment. The design of the monitoring (frequency,
number of sampling sites, method of sampling, procedure
in regard of deviations etc.) is not specifically mandated;
however, the common aim is to recognize any deviation
of the validated state.
The necessity of monitoring the environment as a
key element of a quality assurance program is widely
accepted. Air, surfaces and personnel are all identified as
contamination risk sources for the environment. To come
Aseptic
processing using
isolator systems
minimizes the extent
of personnel
involvement and
separates the
external cleanroom
environment from
the aseptic
processing line.
A very high integrity
can be achieved in a
well-designed unit.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
Page 12
to reasonable limits, the rooms of the production areas have
firstly to be classified depending on the production step.
Limits of air, surfaces and personnel are proposed under
consideration of the official recommendations. There are
separate requirements for non-viable air particles, and for
viable organisms, and the time when the measurements are
performed (either at rest, or in operation). The differences
determine the nomenclature for clean rooms. Both
personnel and material flow should be optimized to prevent
unnecessary activities that could increase the potential for
introducing contaminants to exposed product, container
closures or the surrounding environment. Air (including
purified air) is a main source for contamination. Per EU GMP,
viable airborne particles have to be identified and regarded
in batch release. Surfaces which have immediate contact
with the product are highly critical. Indirect transfer of
particles from surfaces via air must also be taken into
account. The design of the facility (smooth surfaces without
unevenness and tears) is important to avoid contamination
and support the success of sanitization procedures.
6. Quality Control, Approach & Audits
Although quality is the responsibility of all personnel
involved in manufacturing, it is highly recommended that
individual(s) who are assigned to perform QC functions are
independent of manufacturing responsibilities, especially for
the cumulative review and release of phase 1 investigational
drug batches.
The CDMO engaged in the manufacture of phase 1
investigational drugs should follow written manufacturing
and process control procedures that provide for the
following records:
• A record of manufacturing data that details the
materials, equipment, procedures used, and any
problems encountered during manufacturing.
Production records should be sufficient to replicate
Good quality systems
produce quality
products. For that to
happen, the operators
must be well-trained,
and the proper
personnel must review
the manufacturing
documentation. Every
manufacturer should
establish a written plan
that describes the role
of and responsibilities
for the QC function.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage FormsEstablishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
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the manufacturing process. Similarly, if the
manufacture of a phase 1 investigational drug batch
is initiated but not completed, the record must
include an explanation of why manufacturing
was terminated;
• A record of changes in procedures and processes
used for subsequent batches along with the
rationale for any changes; and
• A record of the laboratory (quality control and
microbiological) that have been implemented
(including written procedures) for the production
of sterile-processed phase 1 investigational drugs.
In the early stages of drug development, processing
parameters will be adjusted to meet efficiency targets
better and/or overcome processing hurdles. The CDMO
making these adjustments should have a formal change
control system that allows the client to present this
documentation to the FDA (or other agency) during
later stage filings.
Proper QC documentation also includes a Quality
Agreement. The quality agreement should define
expectations between the CDMO and the sponsor
to review and approve documents, and how they will
communicate with each other, both verbally and in writing.
It also should describe how changes may be made to
standard operating procedures, manufacturing records,
specifications, laboratory records, validation documentation,
investigation records, annual reports, and other documents
related to products or services provided by the contract
facility. The quality agreement should also define owners’
and contract facilities’ roles in making and maintaining
original documents or true copies in accordance with cGMP.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
Page 14
It should explain how those records will be made readily
available for inspection. The quality agreement also should
indicate that electronic records will be stored in accordance
with cGMP and will be immediately retrievable during the
required record-keeping time frames established in
applicable regulations.
Laboratory ControlsLaboratory tests used in manufacturing (e.g., testing of
materials, in-process material, packaging, drug product)
should be scientifically sound (e.g., specific, sensitive, and
accurate), suitable and reliable for the specified purpose.
Tests must be performed under controlled conditions
and follow written procedures describing the testing
methodology. Records of all test results, procedures,
and changes in procedures, must be maintained. The main
purpose of laboratory testing of a Phase 1 investigational
drug is to evaluate quality attributes including those that
define its identity, strength, potency, and purity, as
appropriate. Specified attributes should be monitored,
and acceptance criteria applied appropriately. For known
safety-related concerns, specifications should be established
and met. For some Phase 1 investigational drug attributes, all
relevant acceptance criteria may not be known at this stage
of development as this information will be reviewed in the
IND submission.
To ensure reliability of test results, calibration and
maintenance of laboratory equipment at appropriate
intervals according to established written procedures is
required. Personnel verify that the equipment is in good
working condition when samples are analyzed (e.g., system
suitability). A representative sample from each batch of
Phase 1 investigational drug should be retained. Retention
of both the API and Phase 1 investigational drug in
containers used in the clinical trials is essential. The sample
should consist of a quantity adequate to perform additional
testing or investigation if required at a later date (e.g., twice
the quantity necessary to conduct release testing, excluding
testing for pyrogenicity and sterility). Storage and
retention the samples for at least two years following
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Page 15
clinical trial termination, or withdrawal of the IND application
is recommended.
Finally, initiation of a stability study using representative
samples of the phase 1 investigational drug to monitor the
stability and quality of the phase 1 investigational drug
during the clinical trial (i.e., date of manufacture through
date of last administration) should be performed under ICH
temperature, humidity and light storage conditions.
AuditsA drug sponsor should always visit the CDMO’s site during
the evaluation process. This visit gives the drug developer a
good overview of how the CDMO works. Touring the facility
shows if it is a clean and functioning facility. Evaluate
whether the staff grasps the scope of your project, and
determine whether the scientists have familiarity with the
product type. Drawing on a CDMO’s experience can save
time and potentially deliver a better outcome. For instance, a
sponsor may believe that filling their product in a multi-dose
vial is the best administration method for a clinical setting.
However, this practice could lead to errors in dosing, loss of
extremely scarce product, and potentially determining the
path forward for container stability. In the early stages
of drug development, processing parameters will be
adjusted to meet efficiency targets better and/or overcome
processing hurdles. The CDMO making these adjustments
should have a formal change control system that allows the
client to present this documentation to the FDA (or other
agency) during later stage filings. After a successful site
visit, the next step is to conduct an in-depth audit.
During the audit you will review documentation systems
and discuss the project in more depth. All information and
discussions should be viewed from a quality standpoint.
First, learn about the company’s history, size, services,
financial stability, future plans for growth and technological
innovations. Then determine the training of personnel and
the expertise level of the staff. Find out about the Quality
Assurance and Quality Control systems, manuals, reviews
and methodology; also determine certifications, document
management, procedures and problem solution systems,
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
Page 16
and equipment maintenance and calibrations. Also, look
at measurements/metrics for monitoring and controls,
deviations (the number and significance of them), technical
transfer controls, capabilities, test methods and validations,
material controls and inspections, supplier and material
qualifications, purchasing controls, and laboratory controls.
Determine the GMP compliance history, and SOP (Standard
Operating Procedures) records. From this review a drug
developer will be able to determine if a CDMO has the
technological knowledge, compliance record, and experience
to provide solutions to problems and be able to complete
documentation in a timely fashion.
7. Personnel & Training
Double gloves are often used in industrial practice, as a
result of the dressing technique (the second pair of gloves is
worn after finalizing the dressing). Some aspects for aseptic
technique and behavior in the clean room are mentioned
in the FDA Guidance 2004. Very important for aseptic
manufacturing process are the detailed SOPs of the CDMO
such as aseptic operation, gowning room cleaning as well as
personnel and room environmental monitoring procedures.
Depending on the room classification or function,
personnel gowning may be as limited as lab coats and
hairnets, or as extensive as fully enveloped in multiple
layered bunny suits with self-contained breathing
apparatus. Cleanroom clothing is used to prevent
substances from being released off the wearer’s body
and contaminating the environment. The cleanroom
clothing itself must not release particles or fibers to prevent
contamination of the environment by personnel. Cleanroom
garments include boots, shoes, aprons, beard covers,
bouffant caps, coveralls, face masks, frocks/lab coats,
gowns, glove and finger cots, hairnets, hoods, sleeves
and shoe covers. The type of cleanroom garments used
should reflect the cleanroom and product specifications.
Personnel are the main
source of contamination
of clean rooms with
microorganisms. The
education and training of
the personnel, the
garments, the dress
procedures, the
rules for entry, and the
behavior inside the clean
rooms are important
factors (see EU GMP
Guide Annex 1, ISO 13408-
1, and FDA Guidance).
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Page 17
Low-level cleanrooms may only require special shoes having
completely smooth soles that do not track in dust or dirt.
However, shoe bottoms must not create slipping hazards
since safety always takes precedence. A cleanroom suit
is usually required for entering a cleanroom. Class 10,000
cleanrooms may use simple smocks, head covers, and
booties. For Class 10 cleanrooms, careful gown wearing
procedures with a zipped cover all, boots, gloves and
complete respirator enclosure are required.
8. Process Simulation Validation
All manufacturing procedures in a pharmaceutical
manufacturing operation must be validated - according
to European Pharmacopoeia and FDA guidelines. This
is especially important for aseptic manufacturing of
parenteral dosage forms, where contamination poses a
significant patient risk. Process validation includes checks
on the process by means of process simulation tests using
microbial growth media (i.e., media fill tests). Since, in
pharmaceutical production, validated methods have been
already used for sterilizing equipment, processing air and
water and filtration techniques, media fill validation is very
much focused on the aseptic technique of the human
operator. Intensive training and education of personnel is
required in order to ensure that media fill validation is
recognized as a means of checking sterility level of aseptic
processing. According to all guidelines, process simulation
with media fill is state-of-the-art for validation of an
aseptic manufacturing process. Media fill means that a
microbiological nutrient media will be filled into a container
closure system (ampules, vials, etc.) instead of the
actual product. The filled container closure systems are
incubated under defined parameters and finally checked for
microbiological contamination. This is to demonstrate that
rooms, equipment and personnel are able to manufacture a
product with very low contamination rate.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
Page 18
The EU GMP Guide provides more details on this issue:
“Validation of aseptic processing should include a process
simulation test using a nutrient medium (media fill) ...
The process simulation test should imitate as closely as
possible the routine manufacturing process and include
all the critical subsequent manufacturing steps”.
The validation covers filling of media, environmental
monitoring, and incubation and evaluation of the filled
vials. Additionally the growth promotion properties of the
nutrient must be demonstrated. Microbiological examination
of positive vials, bio-burden examination of the materials
used and identification of contaminants are as well issues
that need to be considered. The simulation should consider
such conditions which simulate the highest risk (worst case)
of maximum expected and permitted loads. Examples for
worst case conditions are defined in ISO 13408. For example,
for vial dimension and filling speed, the worst condition is
the largest vial with the longest filling time. All interventions
and measures of the usual process should be simulated in
media fill. For example manual control of the filling volume,
change in personnel, and performance of environmental
monitoring. Even technical interruptions should be
considered (lack of air system, stopping of the filling
process, etc).
Liquid nutrient growth medium, capable of
supporting a wide range of microorganisms, is prepared,
sterilized, and filled in simulation of a normal manufacturing
process that includes compounding, sterile filtration,
in-process controls, sterilization of manufacturing process,
materials (garments, primary containers, filling equipment),
cleaning and sterilization process (e.g., cleaning in place -
CIP / sterilization in place - SIP) and filling. The sealed
containers of medium thus produced are then incubated
under prescribed conditions and subsequently examined
for evidence of microbial growth. If the media fill reflects
the standard procedure of product filling, the contamination
rate or contamination probability may be used as indicator
for the safety of the production process. Comprehensive
control of production environment, personnel, and
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Page 19
installations, influencing the overall hygienic state of
manufacturing processes will be performed. Since, in
pharmaceutical production, validated methods have been
already used for sterilizing equipment, processing air and
water and filtration techniques, media fill validation is very
much focused on the aseptic technique of the human
operator. Intensive training and education of personnel is
required in order to ensure that media fill validation is
recognized as a means of checking sterility level of
aseptic processing.
Preparation of Media FillLiquid nutrient growth medium, capable of supporting a
wide range of microorganisms, is prepared, sterilized, and
then filled to simulate a normal manufacturing process that
includes compounding, sterile filtration, in-process controls,
sterilization of manufacturing process, materials (garments,
primary containers, filling equipment), and filling. The sealed
containers of medium thus produced are then incubated
under prescribed conditions and subsequently examined for
evidence of microbial growth. If the media fill reflects the
standard procedure of product filling, the contamination rate
or contamination probability may be used as indicator for
the safety of the production process.
Environmental monitoring, comprising airborne counts,
particle counts, and hygiene status of personnel and
materials - e.g., balances and compounding vessels -
is conducted during the weighing and compounding of
materials. Prior to filtration, the pH-value of the nutrient
broth is checked and in-process controls (IPC) on
identity, clarity, and bioburden are conducted. Samples
are controlled for analytical and microbiological controls
like that of any other product. Holding and process times
are documented and may be prolonged for validation
purposes. The bulk solution is sterile-filtered using the same
filter material as in normal aseptic processing. Filter integrity
is checked prior to and after use. Environmental monitoring
is conducted at this processing step. Prior to filling, primary
Media fills, or
process simulation
technique, is
generally accepted
as the procedure to
validate aseptic
manufacturing
processes.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
Page 20
containers are sterilized and depyrogenized, the filling line is
cleaned and sterilized (CIP/SIP) or transfer lines and dosage
pumps are sterilized separately.
Number of Fill Units and Filling Process DurationAccording to FDA Guidance the minimum number of filled
units of media fill is 3,000 units (to reach a confidence level
of 95% for demonstration of a contamination rate of less
than 0.1%). For batch sizes smaller than 3,000 units,
smaller numbers are acceptable (requirements are given
in ISO 13408 and EU GMP Guide Annex 1). For small batch
sizes (for example products used for clinical trials) at least
the actual batch size should be simulated during media fill.
For very large batches, it is recommended to simulate media
fill with 1% of the actual daily batch size. The vials with the
smallest and the biggest size should be regarded in media
fill. Table 2 gives the minimum units require required for a
media fill both for initial qualification and re-qualification
as well as the acceptable warning/action limits.
Table 2. First Qualification and Re-Qualification: Warning and
Action Limits in Media Fill According to ISO 13408-1
production batch number of units
First qualification
Requalification
minimum number of medium fill runs
minimum number of total filled units
warning limit / run
action limit / run
< 500
≥ 500 - 2999
≥ 3000
≥ 3
≥ 3
3
5,000
5,000
9,000
1
1
1
2
2
2
< 500
≥ 500 - 2999
≥ 3000
≥ 3
1
1
maximum batch size
maximum batch size
3,000
1
1
1
2
2
2
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Page 21
Analytical Method ValidationThe extent of analytical procedures and methods validation
necessary will vary with the phase of the IND. Hence the
CDMO may elect to take a fundamental approach to
validation or qualification when appropriate. The main
goal of performing “staged’ validation in the early drug
development is to provide test procedures that are reliable,
able to support clinical studies, and evaluate the safety
of the product. The methods should use appropriate
parameters and sound scientific judgment, sufficient
information is defined as to ensure proper identification,
quality, purity, strength, and/or potency. The validation data
should be retained to link analytical procedures used in early
phase/pivotal clinical studies and a formal validation report
with change control may not be required. A brief summary
of the validation studies is recommended to be submitted
in the original IND.
The suitability of an analytical procedure (e.g., USP/NF, the
Official Methods of Analysis of AOAC International, or other
recognized standard references) should be verified under
actual conditions of use. Information to demonstrate that
USP/NF analytical procedures are suitable for the drug
product or drug substance should be included in the
submission and generated under a verification protocol.
The verification protocol should include, but is not limited
to: (1) compendial methodology to be verified with
predetermined acceptance criteria, and (2) details of the
methodology (e.g., suitability of reagent(s), equipment,
component(s), chromatographic conditions, column,
detector type(s), sensitivity of detector signal response,
system suitability, sample preparation and stability). The
procedure and extent of verification should dictate which
validation characteristic tests should be included in the
protocol (e.g., specificity, LOD, LOQ, precision, accuracy).
Considerations that may influence what characteristic tests
should be in the protocol may depend on situations such as
whether specification limits are set tighter than compendial
acceptance criteria.
Establishing cGMP Manufacturing Capability for Phase 1 Sterile, Dispersed, Injectable Dosage Forms
Page 22
Once an analytical procedure (including compendial
methods) is successfully validated (or verified) and
implemented, the procedure should be followed during
the life cycle of the product to continually assure that it
remains fit for its intended purpose. Trend analysis on
method performance should be performed at regular
intervals to evaluate the need to optimize the analytical
procedure or to revalidate all or a part of the analytical
procedure. If an analytical procedure can only meet the
established system suitability requirements with repeated
adjustments to the operating conditions stated in the
analytical procedure, the analytical procedure should be
reevaluated, revalidated, or amended, as appropriate.
Over the life cycle of a product, new information and
risk assessments (e.g., a better understanding of product
CQAs or awareness of a new impurity) may warrant the
development and validation of a new or alternative
analytical method. New technologies may allow for
greater understanding and/or confidence when ensuring
product quality. Applicants should periodically evaluate
the appropriateness of a product’s analytical methods
and consider new or alternative methods.
9. Conclusion
A small CDMO may choose to establish a GMP area
within a “laboratory setting” for the manufacture of drug
product in early development. Also, the use of isolators and
modular cleanrooms provides flexibility for adjusting the
manufacturing process to the product. Also, injectable,
sterile, disperable products can be manufactured aseptically
to avoid a terminal sterilization requirement. The FDA has
provided an amended rule that stresses that the cGMP
requirements of 21 CFR 211 are applicable only to Phase 2
and Phase 3 drugs and has provided guidance on the
requirements for small-scale Phase I cGMP manufacture.
Some of the regulatory burden is lifted for the manufacture
of Phase I materials as long as basic tenets of quality control
and validation are met.
Production of the
first clinical trial materials
for an injectable
pharmaceutical dosage
form is a significant
milestone, and a
challenging one for a
small company. CDMOs
focused on
manufacturing services
for Phase I sterile dosage
forms can provide a
reliable, cost-effective,
and timely solution to
this challenge.
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Page 23
References
Center for Drug Evaluation and Research (CDER), Guidance for Industry, CGMP for Phase 1 Investigational Drugs, 2008.
European Directorate for the Quality of Medicines and Healthcare, European Pharmacopoeia (Ph. Eur), 8th Edition, 2016.
The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products Brussels: 25 November 2008 (rev.) & 25 November 2010 (rev.).
United States Pharmacopoeia, Rockville, MD: <1211> Sterilization and Sterility Assurance of Compendial Articles, in USP 39, NF 34 (2016); <797> Compounding Sterile Preparations, in USP 39, NF 34 (2016); <1116> Microbiological Evaluation of Clean Rooms and Other Controlled environments, in USP 39, NF 34 (2016); <61> Microbial Limits in USP 39, NF 34 (2016); & <1208> Sterility Testing - V alidation of Isolator Systems in USP 39, NF 34 (2016)
CDER, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing - Good Manufacturing Practice, 2004
International Standard Organization: Aseptic Processing of Health Care Products, Part 1, General Requirements, International Standard ISO 13408-1 (2015); & Cleanrooms and Associated Controlled Environments, Part 1, Classification of Air Cleanliness, International Standard ISO 14644-1 (2015)
Pharmaceutical Inspection Co-Operation Scheme (PIC/S), Recommendation on the Validation of Aseptic Processes, PI007-6 (2011)
Parenteral Drug Association (PDA): Process Simulation Testing for Aseptically Filled Products, Technical Report, No 22, (Rev 2011); Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals, Technical Report, No 28, (Rev 2006); Fundamentals of an Environmental Monitoring Program, Technical Report, No 13 ( Rev 2014); & Sterilizing Filtration of Liquids, Technical Report, No 26 (Rev 2008)
www.ascendiapharma.com
For more information contact:
Donald Pennino, Ph.D.donald.pennino@ascendiapharma.com732-640-0058
Jim Huang, Ph.D.j.huang@ascendiapharma.com732-638-4028
Biographies
Jingjun Huang, Ph.D., CEODr. Huang founded Ascendia in 2012 after fifteen years of
pharmaceutical R&D and management experience at Pfizer, Baxter,
AstraZeneca, and most recently Roche. Dr. Huang holds a Ph.D. in
Pharmaceutics from the University of the Sciences in Philadelphia.
He has lead the formulation development efforts for the successful
transition of several oral and parenteral dosage forms from
discovery through formulation, manufacturing, technical transfer
and ultimately commercialization. Dr. Huang’s research interests
are centered on improvement of solubility and dissolution, and
controlled delivery of, poorly water soluble drugs through
nano-emulsion and amorphous solid dispersion technologies.
He has been a reviewer for the Journal of Pharmaceutical Sciences,
International Journal of Pharmaceutics, Journal of Controlled
Release, Drug Development and Industrial Pharmacy, PDA
Journal of Pharmaceutical Science and Technology, Molecular
Pharmaceutics, and Pharmaceutical Research. Currently, he is a
member of American Association of Pharmaceutical Scientists
(AAPS) and American Chemical Society (ACS).
Donald Pennino, Ph.D., VP, QA/ARDDr. Pennino has over 45 years experience in the pharmaceutical,
biotechnology, and medical device industries. He holds a Ph.D. in
Physical Chemistry from Stevens Institute of Technology in Hoboken,
NJ. He has managed, designed and built many analytical, quality
control, and aseptic operation controlled areas over his career.
He has extensive validation expertise, as well as practical drug
development, helping to bring to market many products by
companies such as Novartis, Warner-Lambert, Schering-Plough,
Pfizer, Stryker BioTech, CR Bard, Chiron and Celator. He currently
is working on DoD projects to develop prophylactic vaccines as
defense to potential bioterrorism threats in the US. He also acts
as a consultant to industry providing regulatory solutions in
the area of quality, remediation and compliance.
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