Fundamental of product development from pharmaceutical technology background

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PAK
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THIS WILL OPEN THE GATES OF SUCCESS FOR YOU,
INSHAALLAH AZZAWAJAL.

3. FUNDAMENTAL OF
PRODUCT
DEVELOPMENT
PRESENTED BY
FARWA HUSSAIN
FARZANA NAZAR

4. CONTENTS
• PRODUCT
• PHARMACEUTICAL PRODUCT
• TYPES OF PRODUCT
• BASIC STRATEGIES IN PRODUCT DEVELOPMENT
• OBSTACLES IN PRODUCT DEVELOPMENT
• PROCESS OF PRODUCT DEVELOPMENT
• PRODUCT DEVELOPMENT DRIVERS, CHALLENGES, RISKS,
AND REWARDS
• PRODUCT LIFE CYCLE
• FRAMEWORK OF PRODUCT DEVELOPMENT
• STAGES OF DRUG DISCOVERY AND DEVELOPMENT PROCESS
• STAGES OF PRODUCT DEVELOPMENT

5. STAGES OF PRODUCT
DEVELOPMENT
• Drug discovery
• Preformulation research
• Formulation development
• Process research and development
• Analytical research and development
• Toxicology and drug metabolism

6. • PROCESS RESEARCH AND DEVELOPMENT
• PRODUCT DESIGN
• IMPORTANCE OF PRODUCT DESIGN
• PILOT PLANT SCALE UP TECHNIQUE
• REASONS FOR BUILDING PILOT PLAN
• SIGNIFICANCE
• PRODUCTION
• PACKAGING
• ROLE OF PACKAGING
• QUALITY CONTROL/ASSURANCE
• MARKETING
• CONCLUSION

7. FORMULATION DEVELOPMENT
Formulation development is the process in which different
chemical substance ,including the active drug are combined
to produced medicinal product.
characterization of the individual drug/excipient
interaction is an important part of understanding the
overall behavior of the dosage form. (e.g. shape and
size)

8. 3)TYPE OF FORMULATIONS
Formulations can be categorized according to
the route of administration
Oral Transdermal
Rectal Intraocular
Vaginal Intranasal
Inhalational Parenteral drug products
Topical

9. FORMULATION DEVELOPMENT
Solid dosage forms
• Solid-state reactions in the dosage form can occur.
• If the drug substance is reactive, it may interact with the
excipients.
• On the other hand excipient can induce degradation of drug
substance.
• Types of interactions between drug substance and excipients
are
• Chemical interactions

10. FORMULATION DEVELOPMENT
• Liquid dosage forms
• Liquid formulations span a variety of dosage forms,
including oral liquids and parenteral formulations.
• The excipients are categorized as solvents, thickening
agents, chelating agents, antioxidants, preservatives,
buffers, and bulking agents.
• For liquid formulations, the compatibility study of the
drug/excipient mixture with the packaging system is an
essential activity due to the intimate contact between the
product and the container.

11. DRUG SUBSTANCE/EXCIPIENTS
COMPATIBILITY TESTING
METHODS
• DSC
• Chromatographic analysis
• Micro calorimetry
• X-ray diffraction
• Microscopy

12. DIFFERENTIAL SCANNING
CALORIMETERS
• Differential scanning calorimeters (DSC) measures
temperatures and heat flows associated with thermal transitions
in a material. Common usage includes investigation, selection,
comparison and end-use performance evaluation of materials in
research, quality control and production applications. Properties
measured by instruments’ DSC techniques include glass
transitions, "cold" crystallization, phase changes, melting,
crystallization, product stability, cure / cure kinetics, and oxidative
stability

13. DSC
• Measurement
• Energy is absorbed or released by a sample as it
is heated, cooled, or held at a constant
temperature.
• Utility of data
• Physicochemical compatibility of drug and
excipients.

15. CHROMATOGRAPHIC
ANALYSIS
• Measurement
• Chemical interactions of the sample with the
stationary phase and the mobile phase.
• Utility of data
• Excipients, drug product purity; excipient–drug
substance chemical compatibility.

17. MICRO CALORIMETRY
• Measurement
• Absorbance or release of heat from solution
sample.
• Utility of data
• Physicochemical compatibility of drug and
excipients; solution applications.

19. X-RAY DIFFRACTION
• Measurement
• Scattering of x-ray radiation by a solid sample
• Utility of data
• Polymorph characterization

21. MICROSCOPY
• Measurement
• Magnified appearance of sample
• Utility of data
• Particle size, morphology

23. 4)PROCESS RESEARCH AND
DEVELOPMENT
• Manufacturing process development begins at the
small scale and proceeds to a minimum of 10% full
production scale for pivotal clinical studies and
registration stability studies.
• Ultimately full-scale production batches (sometimes
referred to as demonstration or engineering batches)
are made prior to validation of the process.
• A review of the manufacturing process development
should include an emphasis on the reproducibility of
the critical quality attributes of the drug product.

24. PROCESS RESEARCH AND
DEVELOPMENT
• Other attributes include
• Container closure system
• Drug product microbiological attributes
• Process validation
• Documented evidence that the process,
operated within established parameters, can
perform effectively and reproducibly to
produce a product meeting its predetermined
specifications and quality attributes.

25. 5)ANALYTICAL RESEARCH AND
DEVELOPMENT
• The analytical methods used to test
excipients, reagents, and drug product should
be reviewed.
• Analytical Procedures are validated, and
specifications are justified.
• Assay
• Impurities
• Disintegration
• Dissolution
• Assay methods are developed and formulation

26. 6)TOXICOLOGY AND DRUG
METABOLISM
• Pharmacokinetics And Drug Disposition
• Pharmacokinetic (PK) or ADME
(Absorption/Distribution/Metabolism/Excretion)
studies provide useful feedback.
• These parameters include
• AUC (area under the curve)
• Cmax (maximum concentration of the drug in blood)
• Tmax (time at which Cmax is reached).

27. TOXICOLOGY AND DRUG
METABOLISM
• Preclinical Toxicology Testing And IND
Application
• Preclinical testing analyzes the bioactivity, safety,
and efficacy of the formulated drug product.
• This testing is critical to a drug’s eventual success
and, as such, is scrutinized by many regulatory
entities.
• During the preclinical stage of the development
process, plans for clinical trials and an Investigative
New Drug (IND) application are prepared.

28. TOXICOLOGY AND DRUG
METABOLISM
• The main stages of preclinical toxicology
testing are:
• Acute Studies
• Repeated Dose Studies
• Genetic Toxicity Studies
• Carcinogenicity Studies
• Toxicokinetic Studies

29. TOXICOLOGY AND DRUG
METABOLISM
• Acute Studies
• Acute toxicity studies look at the effects of one
or more doses administered over a period of
up to 24 hours. The goal is to determine toxic
dose levels and observe clinical indications of
toxicity. Usually, at least two mammalian
species are tested. Data from acute toxicity
studies helps determine doses for repeated
dose studies in animals and Phase I studies in
humans.

30. TOXICOLOGY AND DRUG
METABOLISM
• Genetic Toxicity Studies
• These studies assess the likelihood that the
drug compound is mutagenic or carcinogenic.
• DNA damage is assessed in tests using
mammalian cells.
• The Chromosomal Aberration Test and similar
procedures detect damage at the chromosomal
level.

31. TOXICOLOGY AND DRUG
METABOLISM
• Carcinogenicity Studies
• Carcinogenicity studies are usually needed only for
drugs intended for chronic or recurring conditions.
• Toxicokinetic Studies
• These are typically similar in design to PK/ADME
studies except that they use much higher dose
levels. They examine the effects of toxic doses of
the drug and help estimate the clinical margin of

32. CLINICAL TRIALS
• Phase I Clinical Development (Human
Pharmacology)
• Phase I studies are used to evaluate pharmacokinetic
parameters and tolerance, generally in healthy
volunteers.
• These studies include initial single-dose studies, dose
escalation and short-term repeated-dose studies.

33. CLINICAL TRIALS
• Phase II Clinical Development (Therapeutic
Exploratory)
• Phase II clinical studies are small-scale trials to
evaluate a drug’s preliminary efficacy and side-effect
profile in 100 to 250 patients.
• Additional safety and clinical pharmacology studies
are also included in this category

34. CLINICAL TRIALS
• Phase III Clinical Development (Therapeutic
Confirmatory)
• Phase III studies are large-scale clinical trials for
safety and efficacy in large patient populations.
• While phase III studies are in progress,
preparations are made for submitting the New
Drug Application (NDA)

35. CLINICAL TRIALS
• Phase IV clinical trials (post marketing
studies)
• Treatment's risks, benefits, and optimal use is
included.
• Further indications and adverse effects are
identified.
• As such, they are ongoing during the drug's

36. PRODUCT DESIGN AND ITS
IMPORTANCE
• “Product design” is “the initial stage of product development, where
‘global’ agreement is required about the nature of the product to be
developed.”
• Effective product design is considered to have the following
important benefits:
1. To provide clear direction and objectives for the project team
2. To gain buy-in and input from all the key functions at the start of
development (such as pharmaceutical development, safety,
clinical, manufacturing operations, quality assurance, regulatory,
and commercial/marketing)
3. To assess the feasibility of the project in commercial and technical
terms
4. To identify any risks early and hence manage them
5. To avoid wasting valuable resources on developing a product that
is not needed or wanted

37. PRODUCT DESIGN
CONSIDERATIONS
• A useful outcome of the initial product design phase is a product
design report. This should document the careful evaluation of the
following key elements:
1. Target product profile (TPP)/minimum product profile (MPP)
2. Design specification and critical quality parameters
3. Commercial and marketing considerations
4. Technical issues and risk assessment
5. Safety assessment considerations
6. Environmental, health, and safety considerations
7. Intellectual property considerations

38. 1. TARGET PRODUCT
PROFILE/MINIMUM PRODUCT
PROFILE
• A TPP, which defines the product attributes, should be established for the
intended marketed product based on all “customer” and “end-user” needs.
customers and end users include anyone in the supply chain, including both
internal and external customers, such as those in manufacturing and in sales
and marketing, distributors, doctors, nurses, pharmacists, and patients.
• Each customer wants the right product (meeting their quality expectations)
at the right time and at the right price. additionally, each customer will have
his or her own specific requirements.
• The TPP is based on the ideal product characteristics, which are considered
to be desirable, whereas the MPP is based on the minimum product
requirements, which must be met for the product to be viable and worth
developing.

39. 2. DESIGN SPECIFICATIONS AND
CRITICAL QUALITY PARAMETERS
• In addition to the pre-formulation information, there will be other
considerations in the selection of the excipients and packaging components
for the product.
• It may be important to stipulate that any excipient used must be of
parenteral grade, will comply with pharmacopoeial requirements, and be
restricted to those known to be safe and acceptable to the regulatory
authorities.
• This will reduce the risk, compared with using a novel excipient, which might
be questionable to some regulatory authorities. It will also reassure the
safety/toxicology department that no extra toxicological studies will be
required to approve a new excipient.

40. • Finally, it is useful to agree on what the minimum acceptable
shelf life for the product should be. The product will need to be
stable enough to allow time for quality control (QC) testing and
quality assurance (QA) release after manufacture; distribution to
wholesalers, pharmacists, and doctors; and with acceptable
time for storage until prescribed and used by patients.
• Normally, a minimum three-year shelf life at room temperature
(15–30.8c) is targeted.
• However, if the treatment is very novel, it may be possible to
justify a shorter shelf life and/or storage at lower temperatures,
if stability is likely to be a problem.

41. 3. COMMERCIAL AND MARKETING
CONSIDERATIONS
• Any pharmaceutical company’s economic objective must be to
maximize its ROI after launch. therefore, the commercial viability of
a new product to be developed needs to be commercially assessed
at the product design stage to satisfy the company that it will achieve
a satisfactory roi. some of the factors that should be considered in
the evaluation are as follows:
1. development costs
2. timing to market
3. market size (disease prevalence, diagnosis and treatment rates,
market value)
4. competition (current, developing, and impact on future market)
5. unmet medical need (effectiveness of current treatment,
improvements required)
6. pricing and reimbursement (current and future)
7. target

42. 4. TECHNICAL ISSUES AND RISK
ASSESSMENT
• There may be a variety of issues that should be documented
in the product design report to high light the perceived risks
involved in developing the product. Some of these risks will
be related to pharmaceutical development and others to
clinical, safety/toxicology, or other areas.
• For pharmaceutical development, risk may be associated with
the technical challenge anticipated in developing a novel or
complex drug delivery system or manufacturing process.

43. • Information from early preformulation and biopharmaceuticals studies should
indicate the
• Potential problems for drug delivery, formulation development, and
manufacture.
• There may be a lack of in-house expertise, resulting in the need to contract
out the work
• Or the need to develop an in-house capability.
• These issues need to be resolved quickly or else time penalties could be
incurred.
• Other areas of risk include the sources of excipients and packaging
components. Some excipients or packaging components may only be
available from one supplier, with the risk that the supplier could go out of
business.

44. 5. SAFETY ASSESSMENT
CONSIDERATION
• In the interests of rapid product development, it is beneficial to
select well-established excipients that already have regulatory
approval in registered products. in the united states, specific
requirements for “new” excipients are detailed in the U.S. food
and drug administration’s guidance for industry: nonclinical
studies for the safety evaluation of pharmaceutical excipients,
published in may 2005

45. 6. ENVIRONMENTAL, HEALTH, AND
SAFETY CONSIDERATIONS
• There are increasing pressures on the pharmaceutical industry to
use environmentally friendly materials in products, which are
biodegradable or recyclable and do no harm to the environment.
examples are the replacement of cfcs in pressurized metered dose
aerosols and the replacement of polyvinyl chloride (pvc) for
alternative packaging materials in some countries.
• Any special restrictions on the use of materials in the product need
to be identified at the product design stage.
• The choice of appropriate materials to suit product, customer, and
environment may also have cost implications.
• Another aspect is the nature of the candidate drug to be developed.
special handling requirements may be required for a very potent and
potentially hazardous compound.
• There may be implications for the design and purchase of new
facilities or equipment or the training of employees in new

46. 7. INTELLECTUAL PROPERTY
CONSIDERATIONS
• Few pharmaceutical companies would venture into a long and
expensive development program without a strategy for effective
patent protection in place to ensure market exclusivity.
• Patents are legal property that prevents others using the
invention (for 20 years in most countries) in exchange for a full
public disclosure of information.
• The pharmaceutical industry is one of the major users of the
patent system, which requires that three criteria be met to grant a
patent.
• These criteria are novelty, presence of an inventive step, and
industrial applicability.

47. PILOT PLANT SCALE UP
TECHNIQUES:
• As a part of pharmaceutical industry where lab scale formula is
transformed into a viable product by the development of a reliable
practical procedure for manufacture.
SCALE UP:
The art of designing of prototype using the data obtained from the pilot
plant model.
OBJECTIVES:
• Find mistakes on small scale and make profit on large scale.
• To produce physically and chemically stable therapeutic dosage form.
• Review of the processing equipment.
• Guidelines for production and process control.
• Evaluation and validation.
• To provide master manufacturing formula.

48. REASON FOR BUILDING A PILOT
PLAN:
• To evaluate an process of large change in scale up operation.
• To find and examine all by products or waste.
• To produce a trail lot of quantities of material.
• Clinical studies, analytical development, process development,
stability testing.

49. SIGNIFICANCE:
• Examination of formula.
• Review of range of relevant processing equipment.
• Production rate adjustment.
• Idea about physical space required. Appropriate records and reports
to support GMP.
• Identification of critical feature to maintain quality.
• The specification of raw material.

50. PRODUCTION:
 Manufacturing in pharmaceutical industry is done in compliance with
the current good manufacturing practice (CGMP) regulations. The
personnel involved are expected to understand GMP at least as it is
applied to their particular area of responsibility.
 The ultimate responsibility of producing a quality product lies with
production department. If a product fails this department is required to
find and correct the problem.
 Depending upon the market demand and production capacity the
production batches are planned.
 The first three batches are called prospective validation batches.
Validation batches confirm that the process parameters are optimum for
product specifications required.

51. PACKAGING:
 Packaging of pharmaceutical products is specifically important from
its stability point of view.
 A degraded product may not only lose its potency but also prove
hazardous to patients' life. Decision on packaging is therefore based
on stability profile of the product.
 Amber colored bottles, for example, are utilized for light- sensitive
products.
 Ease of administration/application makes the product patient friendly.
The applicator supplied with vaginal tablets is a part of its pack and
makes the tablet insertion easy.
 Package insert for patients certainly improve patient compliance.

52.  'Instructions to patients' is an essential part of the pharmaceutical
packaging.
 Instructions like 'for external use only', 'shake well before use', 'apply
with rubbing', 'not to be applied on broken skin', etc. Help the patients to
understand how to use the product.
 The instructions on storage make it sure that the product is stored
properly to ensure the product stability. The expiry date indicates the
deadline before which the, product is best for use.
 Finally; attractive pharmaceutical packs enhance the esthetic value of
the product and, in turn, appeal to patient.
 Pharmaceutical product and package are in close association with each
other.
 Any fault in the package can adversely affect the product.
 Two attributes are most important with regard to package, one is the
expectation from the package to provide protection the product from
temperature, light, moisture, o2 .While other is being inert in itself. Who
guidelines define packaging as process that a bulk material must

53. ROLE OF PACKAGING:
 Protection against light, reactive gases, moisture, microbes, physical
damage, pilferage and adulteration.
 Presentation identification information compatible convenience.
 Presentation help in building the image of a product.
 Package help in identification of the product and various desired
information and displayed as per the label requirement of the
product.
 It should be convenient to use or to administer the product e.g. Eye
drops meter dose inhaler.
 It should be compatible with product and should neither contaminate
the product nor be adversely affected by the product.

54. QUALITY CONTROL AND QUALITY
ASSURANCE:
 The quality control department can monitor production process and
indicate where the process is deviating from control standard, supply
statistical data and constructive comments and help in producing
quality product.
 Thus the job of quality control department is to take samples at every
step during production and evaluated them for the desired
specification.
 Actually this department is responsible for batch-to-batch uniformity
and reproducibility of quality products.

55. MARKETING:
• Marketing the product aggressively is a specialized function.
• A well-organized, competent marketing team with excellent product
knowledge and effective communication skills should be an
invaluable asset for any organization, which holds true for
pharmaceutical industry as well.

56. CONCLUSION;
• Principally a dosage form is formulated to achieve predictable therapeutic
response of the drug included in the formulation.
• Pre formulation studies , if carried out properly, play a important role in
anticipating the formulation problems
• . This inter-relationship of pre- formulation and formulation in context of
pharmaceutical product development is expressed in figure.

57. THE INTER RELATIONSHIP OF
PREFORMULATION AND
FORMULATION

58. • Preformulation helps in indicating the feasibility of the formulation of
the desired dosage farm , selection of excepients , process variables
and storage conditions of the final formulation .It also saves a
considerable labour ,time and energy and thus makes formulation
commercially profitable.
• Selection of correct excipient in correct proportion is an impotant step
in formulation development.It is a well established fact that they may
interact with the drug and other excipients in the formulation and
reduce the effectiveness of the dosage farm.
• Examples of interaction ;incompatibility of lactose and amine drugs in
presence of moisture and stearates results in brownish discolouration
of tablet and is called “ mailard reaction” .Some times the excipients
have additive effects as well like EDTA enhances the antibacterial
activity of benzalkonium chloride.
• Other vitally important factor is the processing parameters .
processing parameters are governed by physicochemical properties
of the material.

59. • Finally it must be kept in mind that a quality dosage farm is not
always a commercially successful one.
• A product with a predictable and reproducible pharmacological
response and excellent stability can be considered a quality
product.
• That is not sufficient , however ,for its commercial success .
• Cost esthetic value and ease of administration /application are
the other factors , which along with two previously discussed
ones influence acceptability of the product to both prescribers
and patients.

60. REFERENCES:
• Pharmaceutical product development by N.K Jain 2nd edition
• Cooper & Gunn’s tutorial pharmacy 6th edition
• Pharmaceutical dosage form &drug delivery by Ram I Mahatu 2nd
edition
• The theory and practice of industrial pharmacy by Leon Lachman

61. THANK YOU