55 Drug Product

Development in the
Pharmaceutical Industry
GURVINDER SINGH REKHI, LEON SHARGEL

I. INTRODUCTION
A. Active pharmaceutical ingredient (API)
1. A drug substance is the API or component that produces pharmacological activity.
2. The API may be produced by chemical synthesis, recovery from a natural product, ­enzymatic
­reaction, recombinant DNA technology, fermentation, or a combination of these processes.
­Further purification of the API may be needed before it can be used in a drug product.
3. A new chemical entity (NCE) is a drug substance with unknown clinical, toxicologic, physical,
and chemical properties. In addition, the U.S. Food and Drug Administration (FDA) considers an
NCE as an API that has not been approved for marketing in the United States.
4. The identity, strength, quality, and purity of a drug substance depend on proper control of the
manufacturing and synthetic process.
B. Drug product
1. A drug product is the finished dosage form (e.g., capsule, tablet, injectable) that contains the
API, generally in association with other excipients, or inert ingredients.
2. The excipients in the drug product may affect the functionality and performance of the drug
product, including modifying the rate of drug substance release, improving drug stability, and
masking the drug taste.
3. Different approaches are generally used to produce drug products that contain NCEs, product
line extensions, generic drug products, and specialty drug products.
C. New drug product development
Drug products containing NCE are developed sequentially in the following phases:
1. Preclinical. Animal pharmacology and toxicology data are obtained to determine the safety and
efficacy of the drug. Because little is known about the human and the therapeutic/toxicologic
­potential, many drug products will not reach the marketplace. No attempt is made to develop a
­final formulation during the preclinical stage. Nonclinical studies are nonhuman studies that
may continue at any stage of research to obtain additional information concerning the pharma-
cology and toxicology of the drug.
2. Phase I
a. An investigational new drug (IND) application for human testing is submitted to the FDA.
Clinical testing takes place after the IND application is submitted.
b. Healthy volunteers are used in phase I clinical studies to determine drug tolerance and toxicity.
c. For oral drug administration, a simple hard gelatin capsule formulation containing the API is
usually used for IND studies.
d. Toxicologic studies—including acute, chronic, subchronic, and mutagenicity—and other such
studies in various animal species are planned during this phase.
1074
 Drug Product Development in the Pharmaceutical Industry 1075

3. Phase II
a. A limited number of patients with the disease or condition for which the drug was developed
are treated under close supervision.
b. Dose–response studies, bioavailability, and pharmacokinetics are performed to determine the
optimum dosage regimen for treating the disease.
c. Safety is measured by attempting to determine the therapeutic index (ratio of toxic dose to
effective dose).
d. A drug formulation having good physicochemical stability is developed.
e. Chronic toxicity studies are started in two species; such studies normally last more than
2 years’ duration.
4. Phase III
a. Large-scale, multicenter clinical studies are performed with the final dosage form developed
in phase II. These studies are done to determine the safety and efficacy of the drug product in a
large patient population who have the disease or condition for which the drug was developed.
b. Side effects are monitored. In a large population, new toxic effects may occur that were not
evident in previous clinical trials.
5. Submission of a new drug application (NDA). An NDA is submitted to the FDA for review and
approval after the completion of clinical trials that show to the satisfaction of the medical com-
munity that the drug product is effective by all parameters and is reasonably safe as demonstrated
by animal and human studies.
6. Phase IV
a. After the NDA is submitted, and before approval to market the product is obtained from the
FDA, manufacturing scale-up activities occur. Scale-up is the increase in the batch size from
the clinical batch, submission batch, or both to the full-scale production batch size, using the
finished, marketed product.
b. The drug product may be improved as a result of equipment, regulatory, supply, or market
demands.
c. Additional clinical studies may be performed in special populations, such as the elderly, pedi-
atric, and renal impaired, to obtain information on the efficacy of the drug in these subjects.
d. Additional clinical studies may be performed to determine if the drug can be used for a new
indication or additional labeling indications.
7. Phase V
a. After the FDA grants market approval of the drug, product development may continue.
b. The drug formulation may be modified slightly as a result of data obtained during the manu-
facturing scale-up and validation processes.
c. Changes in drug formulation should always be within the scale-up and post-approval change
(SUPAC) guidelines.
D. Product line extensions are dosage forms in which the physical form or strength, but not the use or
indication, of the product changes. Product line extension is usually performed during phase III, IV, or V.
1. Developing a transdermal patch when only tablets have been available, for example:
•  Progesterone
•  Nicotine
•  Estradiol
•  Nitroglycerin
2. Additional strengths—as long as these strengths are within the total daily dose, for example:
•  Ibuprofen
3. Controlled-release or modified-release dosage forms when only an immediate-release dosage
form is available. This is an ongoing project for all brand companies; almost every NCE has or will
eventually have a modified-release dosage form of the immediate-release product.
E. Biologic products
1. A biologic product is any virus, serum, toxin, antitoxin, vaccine, blood, blood component or de-
rivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure
of diseases or injuries.
2. Biologic products are a subset of drug products, distinguished by their manufacturing processes
(biologic vs. chemical). In general, the term drugs include biologic products.
1076 Chapter 55      I. E

3. Biologic license application (BLA). Biologic products are approved for marketing under the
provisions of the Public Health Service (PHS) Act.
F. Generic drug products
1. After patent expiration of the API and/or brand drug product, a generic drug product may be
marketed. A generic drug product is therapeutically equivalent to the brand-name drug product and
contains the same amount of the drug in the same type of dosage form (e.g., tablet, liquid, injectable).
2. A generic drug product must be bioequivalent (i.e., have the same rate and extent of drug ­absorption)
to the brand drug product. Therefore, a generic drug product is expected to give the same clinical
response (Chapter 6). These studies are normally performed with healthy human volunteers.
3. Some generic products are not absorbed; for some others, bioequivalence is not a good ­marker.
Under those conditions, comparative clinical trials or studies with pharmacodynamic end
points are considered to measure the equivalence of two products. Inhalation products and non-
absorbed drug products fall into this category.
4. The generic drug product may differ from the brand product in physical appearance (i.e., size,
color, shape) or in the amount and type of excipients used in the formulation.
5. A generic drug product may not differ in both the qualitative and the quantitative compositions
for liquids, injectables, semisolids, transdermal patches, inhalation products, and ophthalmic
products, unless adequate safety studies have been performed.
6. Before a generic drug product is marketed, the manufacturer must submit an abbreviated new
drug application (ANDA) to the FDA for approval. Because preclinical safety and efficacy
­studies have already been performed for the NDA-approved brand product, human bioequiv-
alence ­studies, instead of clinical trials, are generally required for the ANDA. The chemistry,
­manufacturing, and control requirements for the generic drug product are similar to those for the
­brand-name drug product.
G. Specialty drug products are existing products developed as a new delivery system or for a new
therapeutic indication. The safety and efficacy of the drug product were established in the initial
NDA-approved dosage form. For example, the nitroglycerin transdermal delivery system (patch) was
developed after experience with nitroglycerin sublingual tablets.

II. PRODUCT DEVELOPMENT. For each drug, various studies are required to develop a safe,
effective, and stable dosage form.
A. New chemical entities
1. Preformulation is the characterization of the physical and chemical properties of the active drug
substance and dosage form. The therapeutic indication of the drug and the route of administra-
tion dictate the type of drug product or drug delivery system (e.g., immediate release, controlled
release, suppository, parenteral, transdermal) that needs to be developed.
a. Preformulation activities are usually performed during the preclinical stage. However, these
activities may continue into phases I and II.
b. The following information is obtained during preformulation.
(1) Physical, including particle size and shape, crystallinity, polymorphism, density, surface
area, hygroscopicity (ability to take up and retain moisture), and powder flow
(2) Solubility, including intrinsic dissolution, pH solubility profile, and general solubility
characteristics in various solvents
(3) Chemical, including surface energy, pH stability profile, pKa, temperature stability (dry
or under various humidity conditions), and excipient interactions
(4) Analytical methods development, including development of a stability indicating ­method
(measures both the API and the related substances), and cleaning methods
2. Formulation development is a continuing process. Initial drug formulations are developed for
early clinical studies. When the submission of an NDA is considered, the manufacturer attempts
to develop the final (marketed) dosage form. The dose of the drug and the route of administration
are important in determining the modifications needed.
a. Injectable
(1) A final injectable drug product is usually developed in the preclinical phase.
(2) Major concerns include the stability of the drug in solution and the sterility of the product.
(3) Because few excipients are allowed in injectable products, the formulator must choose a
final product early in the development process.
 Drug Product Development in the Pharmaceutical Industry 1077

(4) If the formulation is changed, bioavailability studies are not required for intravenous
­injections because the product is injected directly into the body.
(5) Formulation changes may require acute toxicity studies.
b. Topical (for local application) includes antibacterials, antifungals, corticosteroids, and local
anesthetics.
(1) The final dosage form for a topical drug product is usually developed during phase I
­because any major formulation changes may require further clinical trials.
(2) The release of the drug from the matrix is measured in vitro with various diffusion cell models.
(3) Significant problems encountered with locally acting topical drug products include local
irritation and systemic drug absorption.
c. Topical (for systemic drug absorption) includes drug delivery through the skin (t­ransdermal),
mucous membranes (intranasal), and rectal mucosa.
(1) A prototype formulation is developed for phase I.
(2) A final topical drug product is developed during phase III after the available technology
and desired systemic levels are considered.
d. Oral
(1) Prototype dosage forms are often developed during the preclinical phase to ensure that
the drug is optimally available and that the product dissolves in the gastrointestinal tract.
(2) In the early stages of product development, hard gelatin capsule dosage forms are often
developed for phase I clinical trials. If the drug shows efficacy, the same drug formulation
may be used in phase II studies.
(3) Final product development begins when the drug proceeds during phase II and before
initiating phase III clinical studies.
3. Marketed product. Considerations in the development of a final dosage form include the following:
a. Color, shape, size, taste, viscosity, sensitivity, skin feel, and physical appearance of the ­dosage form
b. Size and shape of the package or container
c. Production equipment
d. Production site
e. Country of origin in which the drug is to be manufactured
f. Country in which the drug will be marketed
B. Product line extensions are generally defined as drug products containing an NDA-approved drug
in a different dosage strength or in a different dosage form (e.g., modified release, oral liquid).
1. Oral product line extensions
a. The simplest dosage form to develop is a different dosage strength of a drug in a tablet or
­capsule. Only bioequivalence studies are needed.
b. A modified-release dosage form is more difficult to develop when only an immediate-release
dosage form exists. Clinical trials are normally required.
c. Considerations in developing these dosage forms are similar to those for the final drug ­product
(see II.A.3).
d. Marketing has a role in the choice of the dosage form.
e. Because the original brand drug product information contributes to the body of knowledge
about the drug, no preformulation is needed. All other factors considered for the original
product are similar. If the relation between in vitro dissolution and in vivo bioavailability is
known, the innovator can progress to a finished dosage form relatively quickly.
f. Regulatory approval is based on the following:
(1) Analytical and manufacturing controls
(2) Stability information
(3) Bioavailability and bioequivalence studies
(4) Clinical trials (in the case of modified-release dosage forms)
g. A new therapeutic indication for a drug requires new efficacy studies and a new NDA.
2. Liquid product line extensions
a. If the current marketed product is a liquid preparation, then the same factors as for the solid
oral dosage forms are considered (see II.B.1.a–g).
b. If the marketed product is a solid oral dosage form and the product line extension is a liquid,
product development must proceed with caution because the rate and extent of absorption for
liquid and solid dosage forms may not be the same.
1078 Chapter 55      II. B

c. Regulatory approval requires

(1) analytical and manufacturing controls;
(2) stability information;
(3) Bioavailability and bioequivalence studies
(4) safety studies (e.g., depending on the drug substance, local irritation); and
(5) clinical trials, if the rate and extent of drug absorption are drastically altered from the
original dosage form.
C. Combination products are made up of two or more regulated components (e.g., drug/drug, drug/
device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or
otherwise combined or mixed and produced as a single entity.
1. These may be two or more separate products packaged together in a single package or as a unit
and may be composed of drug and device products, device and biologic products, or biologic and
drug products.
2. An example is an inhalation steroid (e.g., beclomethasone inhalation aerosol) in which the device
component is important for delivery of the steroid.

III. PREAPPROVAL INSPECTIONS (PAIs)

A. The manufacturing facility is inspected by the FDA after an NDA, abbreviated antibiotic drug appli-
cation (AADA), or ANDA is submitted and before the application is approved.
B. A PAI may also be initiated if a major change is reported in a supplemental application to an NDA,
AADA, or ANDA.
C. During the PAI, the FDA investigator
1. performs a general current good manufacturing practice (cGMP) inspection relating specifically
to the drug product intended for the market;
2. reviews the development report to verify that the drug product has enough supporting documen-
tation to ensure a validated product and a rationale for the manufacturing directions;
3. consults the chemistry, manufacturing, and control (CMC) section of the NDA, AADA, or ANDA
and determines the capability of the manufacturer to produce the drug product as described;
4. verifies the traceability of the information submitted in the CMC section to the original labora-
tory notebooks, electronic information, and batch records;
5. verifies and ensures that all the quality systems are in place to manufacture the product so it retains
the identity, strength, quality, and purity of the drug product that were approved by the center; and
6. recommends approval for the manufacture of the drug product based on the status of the
inspection.

IV. SCALE-UP AND POSTAPPROVAL CHANGES (SUPACs)

A. Purpose. These guidelines are intended to reduce the number of manufacturing changes that re-
quire preapproval by the FDA. The guidelines are published by the FDA on the Internet (http://www.
fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/).
B. Function. These guidelines provide recommendations to sponsors of NDAs, AADAs, and ANDAs
during the postapproval period when
1. making slight changes in the amount of the excipient to aid in the processing of the product
­during scale-up,
2. changing the site of manufacture,
3. scaling up (increasing) or scaling down (decreasing) the batch size of the formulation, and
4. changing the manufacturing process or equipment.
C. The FDA must be notified about a proposed change to a drug product through different regulatory
documentation, depending on the type of change proposed.
1. Annual report. Changes that are unlikely to have any detectable effect on formulation quality and
performance can be instituted without approval by the FDA and reported annually. Examples of
these changes include the following:
a. Compliance with an official compendium
b. Label description of the drug product or how it is supplied (not involving dosage strength or
dosage form)
c. Deletion of an ingredient that affects only the color of the product
 Drug Product Development in the Pharmaceutical Industry 1079

d. Extension of the expiration date based on full shelf-life data obtained from a protocol
­approved in the application
e. Container and closure system for the drug product (except a change in container size for non-
solid dosage forms) based on equivalency to the approved system under a protocol ­approved
in the application or published in an official compendium
f. Addition or deletion of an alternate analytical method
2. Changes being effected (CBE) supplement. Changes that probably would not have any detectable
effect but require some validation efforts require specific documentation, depending on the change.
A supplement is submitted, and the change can be implemented without previous ­approval ­(CBE-0)
by the FDA or, in some cases, the FDA has 30 days to review the change ­(CBE-30). The FDA may
reject this supplement. Examples of reasons for submitting a supplement include the following:
a. Addition of a new specification or test method or changes in methods, facilities, or controls
b. Label change to add or strengthen a contraindication, warning, precaution, or adverse reaction
c. Use of a different facility to manufacture the drug substance and drug product (the manu-
facturing process in the new facility does not differ materially from that in the former facility,
and the new facility has received a satisfactory cGMP inspection within the previous 2 years
covering that manufacturing process)
3. Preapproval supplement. Changes that could have a significant effect on formulation quality
and performance require specific documentation. This supplement must be approved before the
proposed change is initiated. Appropriate examples for preapproval supplement are the ­following:
a. Addition or deletion of an ingredient
b. Relaxation of the limits for a specification
c. Establishment of a new regulatory analytical method
d. Deletion of a specification or regulatory analytical method
e. Change in the method of manufacture of the drug product, including changing or relaxing an
in-process control
f. Extension of the expiration date of the drug product based on data obtained under a new or
revised stability testing protocol that was approved in the application
D. When any change to a drug product is proposed, the manufacturer must show that the resultant
drug product is bioequivalent and therapeutically equivalent to the original approved drug ­product
(see Chapter 6).
1. A minor change is a change that has minimal potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness
of the product. If the proposed change is considered minor by the FDA, bioequivalence may be
demonstrated by comparative dissolution profiles for the original and new formulations.
2. A major change is one that has substantial potential to have an adverse effect on the identity,
strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness
of the product. If the proposed change is considered major by the FDA, bioequivalence must be
demonstrated by an in vivo bioequivalence study comparing the original and new f­ ormulations.

V. GOOD MANUFACTURING PRACTICES (GMPs) are regulations developed by the

FDA. GMPs are minimum requirements that the industry must meet when manufacturing, processing,
packing, or holding human and veterinary drugs. These regulations, also known as cGMPs, establish
criteria for personnel, facilities, and manufacturing processes to ensure that the finished drug product has
the correct identity, strength, quality, and purity characteristics.
A. GMPs are described in the Code of Federal Regulations (CFRs), title 21, sections 210 and 211.
B. Drug product quality and drug product performance
1. Drug product quality relates to the biopharmaceutical and physicochemical properties of the
drug substance and the drug product to the in vivo performance of the drug.
2. Drug product performance is the release of the API from the drug product, leading to bioavail-
ability of the API and achieving a desired therapeutic response.
a. The performance of each drug product must be consistent and predictable to assure both
clinical efficacy and safety.
b. Drug product attributes and performance are critical factors that influence product quality.
c. Each component of the drug product and the method of manufacture contribute to quality.
1080 Chapter 55      V. C

C. Pharmaceutical development
1. Quality by Design (QbD) is a systematic, scientific, risk-based, holistic, and proactive approach
to pharmaceutical development that begins with predefined objectives and emphasizes product
and processes understanding and process control.
2. The drug product and manufacturing method must be designed and developed with quality and
the desired final product in mind.
3. To achieve QbD objectives, product and process characteristics important to desired perfor-
mance must be derived from a combination of prior knowledge and experimental assessment
during product development.
4. Critical manufacturing attributes (CMAs) and critical process parameters (CPPs). A critical
quality attribute is a physical, chemical, biological, or microbiological property or characteristic
that needs to be controlled (directly or indirectly) to ensure product quality.
a. The pharmaceutical manufacturer should identify critical manufacturing attributes (CMAs),
CPPs, and sources of variability that ensures the quality of the finished dosage form.
b. The critical quality attributes should be based on clinical relevance.
D. Quality control (QC) unit is the group within the manufacturer that is responsible for establishing
process and product specifications.
1. Specifications are the criteria to which a drug product should conform to be considered having
acceptable quality for its intended use.
2. The QC unit tests the product and verifies that the specifications are met. QC testing includes the
acceptance or rejection of the incoming raw materials, packaging components, drug products,
water system, and environmental conditions (e.g., heating, ventilation, air-conditioning, air qual-
ity, microbial load) that exist during the manufacturing process.
E. Quality assurance (QA) unit is the group within the manufacturer that determines that the systems
and facilities are adequate and that the written procedures are followed to ensure that the finished
drug product meets the applicable specifications for quality.

Study Questions
Directions: Each statement in this section can be correctly 2. The required information contained in a NDA that is
completed by one or more of the suggested phrases. not included in the ANDA consists of
Choose the correct answer, A–E: I. preclinical animal toxicity studies.
A if I only is correct II. clinical efficacy studies.
B if III only is correct III. human safety and tolerance studies.
C if I and II are correct 3. A product line extension contains the NDA-approved
D if II and III are correct drug in a new
E if I, II, and III are correct
I. dosage form.
1. Healthy human volunteers are used in drug II. dosage strength.
development for III. therapeutic indication.
I. phase I testing after the submission of an
investigational new drug (IND) application.
II. generic drug development for an abbreviated
new drug application (ANDA) submission.
III. phase III testing just before the submission of a
new drug application (NDA).
 Drug Product Development in the Pharmaceutical Industry 1081

Directions: Each statement in this section can be correctly 5. The unit within the pharmaceutical manufacturer that
completed by one of the suggested phrases. Choose the ensures that the finished dosage form has met all the
best answer. specifications for its intended use is the
4. The regulations developed by the U.S. Food and (A) analytical methods unit.
Drug Administration (FDA) for the pharmaceutical (B) marketing and sales unit.
industry for meeting the minimum requirements in (C) PAI unit.
the manufacturing, processing, packing, or holding of (D) QA unit.
human and veterinary drugs are known as (E) QC unit.
(A) good manufacturing practices (GMPs). 6. Manufacturers may make a change in the formulation
(B) quality assurance (QA). after market approval. If the change in the formulation
(C) quality control (QC). is considered a minor change, the manufacturer needs
(D) pre-approval inspection (PAI). to report the change to the FDA only in the
(E) scale-up and post-approval changes (SUPACs). (A) annual report.
(B) preapproval supplement.
(C) IND submission.
(D) changes being effected supplement, 30 days
(CBE-30).
(E) no report is required for a minor change.

Answers and Explanations

1. The answer is C (I, II) [see I.C.2.b; I.F.2]. 4. The answer is A [see V].
Phase I testing is the first set of human studies per- Quality control and quality assurance follow GMP
formed during new drug development. Phase I stud- regulations to ensure that the finished product meets
ies establish the tolerance and toxicity of the drug all applicable specifications for quality. The FDA may
in humans. Bioequivalence studies for generic drug inspect a manufacturing site (PAI) before the drug
­development are most often performed in healthy ­application is approved. In addition, the FDA must be
­human volunteers. These studies establish the bio- notified about any proposed changes to an approved
equivalence of the generic drug product against the drug product.
brand drug product. Phase III testing entails large-
5. The answer is E [see V.D].
scale, multicenter clinical studies performed in ­patients
The QC unit performs the appropriate tests on the
with the disease or condition to be treated. Phase III
dosage form. PAI is performed by FDA compliance
studies determine the safety and efficacy of the drug in
inspectors, who examine the pharmaceutical manu-
a large patient population.
facturer and review the procedures and records for
2. The answer is E (I, II, and III) [see I.C.5; I.F.6]. manufacturing the finished dosage form before the
The development of a new drug requires extensive ­administration grants market approval. The ­analytical
toxicity and efficacy testing in animals and humans. development unit develops the analytical methods
The NDA documents all studies performed on the used in testing the drug product.
drug. The ANDA is used for generic drug product
6. The answer is A [see IV.C.1].
submissions. The generic drug product is similar to
All changes in the formulation must be reported to
the ­original brand drug product that has already been
the FDA. A minor change is a change that has mini-
marketed. Because the efficacy, safety, and toxicity of
mal potential to have an adverse effect on the identity,
this drug product have been studied and documented,
strength, quality, purity, or potency of the product as
further studies of this nature are unnecessary.
they may relate to the product’s safety or effectiveness.
3. The answer is C (I, II) [see I.D]. Changes that are unlikely to have any detectable effect
Product line extensions are developed after further on formulation quality and performance can be insti-
studies with the original NDA-approved drug product. tuted without approval by the FDA and need only to be
From these studies, the manufacturer may develop a reported in the annual report.
new dosage form (e.g., controlled-release product) or
a new dosage strength. A new therapeutic indication
requires an NDA.