Fundamental of-product-development

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FUNDAMENTAL OF PRODUCT

DEVELOPMENTPRESENTED BY

FARWA HUSSAINFARZANA NAZAR

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

STAGES OF PRODUCT DEVELOPMENT

• Drug discovery• Preformulation research• Formulation development• Process research and development• Analytical research and development• Toxicology and drug metabolism

• 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

FORMULATION DEVELOPMENTFormulation 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)

3)TYPE OF FORMULATIONS

Formulations can be categorized according to the route of administration Oral TransdermalRectal IntraocularVaginal IntranasalInhalational Parenteral drug

productsTopical

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• physical interactions

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.

DRUG SUBSTANCE/EXCIPIENTS COMPATIBILITY TESTING

METHODS• DSC• Chromatographic analysis• Micro calorimetry• X-ray diffraction• Microscopy

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

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.

CHROMATOGRAPHICANALYSIS

• 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.

MICRO CALORIMETRY

• Measurement• Absorbance or release of heat from

solution sample.

• Utility of data• Physicochemical compatibility of drug and

excipients; solution applications.

X-RAY DIFFRACTION

• Measurement• Scattering of x-ray radiation by a solid

sample

• Utility of data• Polymorph characterization

MICROSCOPY

• Measurement• Magnified appearance of sample

• Utility of data• Particle size, morphology

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.

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.

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 is assayed.

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).

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.• Studies taking place during the preclinical

stage should be designed to support the clinical studies that will follow.


• The main stages of preclinical toxicology testing are:• Acute Studies• Repeated Dose Studies • Genetic Toxicity Studies• Carcinogenicity Studies • Toxicokinetic Studies


• 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.


• 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.


• 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 safety.

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.

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

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)

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 lifetime of

active medical use.

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 team2. 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 terms4. To identify any risks early and hence manage them5. To avoid wasting valuable resources on developing a product that is not

needed or wanted6. To provide a good reference source for the development plan

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 parameters3. Commercial and marketing considerations4. Technical issues and risk assessment5. Safety assessment considerations6. Environmental, health, and safety considerations7. Intellectual property considerations

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.

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.

• 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.

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 costs2. timing to market3. 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

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.

• 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.

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

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 techniques.

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.

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.

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.

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.

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.

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.

'Instructions to patients' is an essential part of the pharmaceutical packaging. Instructions like 'for exter nal 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 undergo to become a finished product.

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.

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.

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.

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 preformulation and formulation in context of pharmaceutical product development is expressed in figure.

THE INTER RELATIONSHIP OF PREFORMULATION AND FORMULATION

• 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.

• 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.

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

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Fundamental of-product-development