Drug RA丨第13章 药物开发研究与生产经验

Chapter 13 Pharmaceutical Development Studies and Manufacturing Experience

The aim of pharmaceutical development is to design a quality product, as well as its manufacturing process, to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. Information from pharmaceutical development studies can be a basis for quality risk management.

It is important to recognize that quality cannot be tested into products; therefore, quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful.

When developing a formulation, it is important to identify attributes critical to the finished product’s quality, taking into consideration its intended usage, route of administration and the specific needs of the intended patient population, e.g., pediatrics,geriatrics. All excipient choices should be justified. Although excipients usually are inactive substances, their safety for the target population should be considered. The potential effect of the active substance’s physicochemical properties (e.g., water content,solubility, particle size distribution, polymorphic or solid-state form) on the finished product’s performance should be evaluated.

Another key issue to be investigated is the active substance’s compatibility with excipients, and container closure systems. For combination products, the compatibility of the devices and/or active substances with each other also should be evaluated.

The knowledge and data acquired from pharmaceutical development studies and experience gained from manufacturing data may be used to support the establishment of the design space, specifications, and manufacturing controls. Other development concepts (namely, quality by design) can include the results of studies using design of experiments (DOE), quality risk assessment and manufacturing controls throughout the lifecycle of the product.

Pre-formulation

Pre-formulation is a group of studies that focus on the physicochemical properties of a new drug candidate that could affect the drug performance and the development of a dosage form and helps researchers choose what ingredients (excipients) should be used in the preparation.1 Formulation studies aim to develop a drug preparation which is both stable, safe and acceptable to the patient.

Pre-formulation studies can be classified into several aspects. First, there is the characterization of fundamental properties, which includes understanding the solubility in different solvents, dissociation constant (pKa), partition or distribution coefficient, pH, permeability, solid state stability, solution state stability, etc.

Second, screening of an appropriate salt, polymorph, solvate forms and amorphous form occurs. Third, an understanding of the derived pre-formulation properties like morphology, particle size, bulk density, etc., must be gained. The last activity performed in pre-formulation studies is the excipients compatibility studies, to investigate the stability of the drug substance in the presence of the excipients.

Overview of Pharmaceutical Development via Quality by Design Principle

The Quality by Design (QbD) development approach starts with a clear definition of the Target Product Profile (TPP) in accordance with patient needs related to dosing, convenience, and compliance, as well as marketing requirements for the intended therapeutic indication.

The product requirements can be divided into the following three aspects (Figure 13-1):

1.Product stability that maintains consistent product qualities before patient use;

2.Manufacturability that the process is capable to yield a drug product with consistent product quality;

3.Patient use during which the product maintains consistent product qualities.

There are a variety of factors that need to be considered to meet the product requirement for each aspect. These factors are summarized in Figure 13-2.

Product Stability

Product stability is largely determined by the molecular properties, which are usually assessed and possibly optimized during lead generation for clinical candidates. Pre-formulation characterization studies are conducted during early development to understand the degradation pathway with respect to stress conditions, as well as formulation variables. For example, the effect of pH on solution stability in the case of biologics is probably the most important factor. It is critical to balance chemical stability, physical stability, thermal stability and solubility in order to identify the optimal pH range for proper dosage form development. If an optimal pH region does not exist for a

feasible solution formulation, a freeze-dried formulation needs to be considered. Alternatively, specific excipients can be added to address particular instability issues and therefore enhance the probability of identifying an optimal pH region.

A critical prerequisite to understand product stability are the critical properties of the active pharmaceutical ingredient (API). In the case of biologics, there could be post-translational modifications that contribute to large lot-to-lot variability during API process development. In the case of chemical drugs, the amorphous nature and/or crystalline form along with interconversion are critical to understanding the final drug product stability. It is extremely useful to establish a correlation between the timing of

API lot history and the various formulation development studies, such as forced degradation, pre-formulation, formulation DOE and prototype stability studies. As a result, the risk of potentially significant lot-to-lot variability of API critical properties is minimized and provides some assurance that formulation development results are representative. Drug products prepared from future API lots would be expected to perform similarly.

Based on API characterization results, a preliminary stability risk assessment should consider the impact of these modifications on the critical quality attributes directly linked to the TPP, as well as the stability growth potential. A second element of the initial formulation risk assessment is investigation of possible impact of formulation parameters and conditions, such as pH, excipients, trace metals, light, etc., on solution formulation stability. The criticality of each of these identified factors can be determined based on forced degradation and pre-formulation study results to help set up the multivariate formulation optimization study.

A comprehensive pre-formulation characterization is not likely to have been completed during the early stage of clinical development. A suitable early phase clinical formulation can be defined by the somewhat limited understanding of molecular properties but supplemented by platform knowledge. In turn the real time clinical and stability experience gathered during clinical trial studies can be an extremely useful consideration to define product stability.

The next step is to optimize the critical formulation variables with respect to those degradations of high risk, which are identified via risk assessment based on pre-formulation and forced degradation studies. A multivariate statistical DOE study is set up to optimize the key formulation parameters with respect to chemical and physical stability. The goal of the DOE study is to develop a formulation suitable for commercial development. In particular, a quantitative model can be developed based on statistical analysis of the results. The DOE results summarized in the context of formulation design space provide a comprehensive understanding of the response of the critical product attributes as a function of the critical formulation variables. Furthermore, this information forms the knowledge base for selection of a commercial solution formulation with sufficient robustness that will likely meet the shelf life stability requirements.

Manufacturability

Different types of products (e.g., chemical drugs versus biologics) are manufactured by very different processes. Manufacturability is again largely determined by the molecular properties. A similar QbD approach as described above for product stability can be utilized to design and develop a manufacturing process that yields a product with consistent quality (Figure 13-3).

A comprehensive comparison of QbD regulatory guidance in major markets is summarized in Table 13-1.

Patient Use

When a drug is prescribed to patients, it is important that the product maintains consistent quality during patient use. For a self-administered drug that may have a complicated process (e.g., a combination product where an auto-injector is involved), detailed step-by-step instructions are usually provided to give directions that are clear and understandable for patients to promote safe and effective use of the drug. The instructions vary significantly depending on the types of diseases and therapy, which is beyond the scope of this chapter. However, the prescribed drugs must meet the label claims under 21 CFR 201.51. Section (g) specifically describes the declaration of net quantity of contents, which shall express an accurate statement of the quantity of contents of the package. Furthermore, in the case of a liquid drug intended for injection the declaration shall comply with the excess volume prescribed by the National Formulary of the US Pharmacopeia. A comparison of the container content regulations and guidelines among the global markets is summarized in Table 13-2.

Pharmaceutical development dossier - 3.2.P.2 CTD organization

The Pharmaceutical Development Section 3.2.P.2 of the Module 3 -Quality of the Common Technical Document (CTD) should describe the knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. This section should include sufficient information in each part to provide an understanding of the development of the drug product and its manufacturing process.

Reference List Drug (RLD) Selection Considerations (for Generics/Hybrids) and Characterization 

US

Food and Drug Administration (FDA) regulations define a listed drug as a new drug product that has been approved for safety and effectiveness under the relevant regulations. FDA identifies in the Orange Book listed drugs that have been designated as RLDs. A listed drug approved for safety and effectiveness that appears in the Active Section of the Orange Book may be eligible to be an RLD.

Europe

For Article 10(1) generic and 10(3) hybrid marketing authorization applications reference must be made to the dossier of a reference medicinal product for which a marketing authorization is or has been granted in the Union on the basis of a complete dossier in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC.3 According to Article 10(1), third subparagraph of Directive 2001/83/EC a generic application can also be submitted in a Member State even if the reference medicinal product has never been authorized in that Member State. In that case, a reference medicinal product in another Member State should be identified, a so-called “European reference medicinal product.”

Test products in an application for a generic or hybrid product or an extension of a generic/hybrid product are normally compared with the corresponding dosage form of a reference medicinal product, if available on the market.

The selection of the reference product used in a bioequivalence study should be based on assay content and dissolution data and is the responsibility of the applicant.4 Unless otherwise justified, the assayed content of the batch used as test product should not differ more than 5% from that of the batch used as reference product determined with the test procedure proposed for routine quality testing of the test product.

Australia

To register a new generic medicine in Australia, you must demonstrate bioequivalence against the Australian reference product. A bioequivalence study using an overseas reference product may be acceptable, provided you can demonstrate identicality between the Australian and overseas reference products by fulfilling specific conditions.

Comparison to RLD Considerations

One of the expectations related to the pharmaceutical section content of a dossier of an abridged application is the discussion on the reference product choice and the comparison and essential similarity proof between the applied and reference products.

Based on Directive 2001/83/EC a generic medicinal product is defined as a medicinal product which has the same qualitative and quantitative composition in active substances as the reference medicinal product. The same qualitative and quantitative composition requirement extends only to the active substance(s) and not to the other ingredients of the product. Though it is advisable to use similar amounts of the same excipients in the composition of test like in the reference product, differences in excipient composition are accepted provided that they do not lead to significant differences as regards safety and efficacy. This is applicable even in the case of immediate release dosage forms, for which although the impact of excipients on bioavailability of highly soluble and completely

absorbable drug substances (e.g., BCS-class I) is considered rather unlikely, it cannot be completely excluded.

Excipients that might affect bioavailability ( e.g. sorbitol, mannitol, sodium lauryl sulfate or other surfactants) should be identified, as well as their possible impact on different aspects of pharmaceutical effect like the gastrointestinal motility, drug permeability or interaction with membrane transporters. Excipients that might affect bioavailability should be qualitatively and quantitatively the same in the test product and the reference product.

In all cases it should be further demonstrated that the excipients included in the formulation of the multisource product are well established for use in products containing that API and that the excipients used will not lead to differences between the comparator and multisource product with respect to processes affecting absorption (e.g., by effects on gastro-intestinal motility or interactions with transport processes) or which might lead to

interactions that alter the pharmacokinetics of the API.

FDA also states that, based on section 21 of the Code of Federal Regulations (CFR), generics and their reference drugs have the same active ingredient(s), strength, dosage form, route of administration and condition of use. The regulations allow for formulation differences, i.e., changes in inactive ingredients (excipients), impurities and residual solvents, if applicants provide information demonstrating that these differences do not affect the safety or efficacy of the proposed drug product.

In addition, the pharmaceutical development section should include an explanation of the choice of the excipient(s). Compatibility of the excipients with active substances and, where relevant, with other excipients, should be established. The excipients chosen,

their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed in relation to the respective function of each excipient.

Container Closure Considerations (Compatibility with Dosage Form) 

General concepts

An essential part of the pharmaceutical development is the choice and evaluation of the appropriate container closure system (CCS). A dossier should describe and discuss the choice and rationale for selection of the container closure system for the commercial product (described in section 3.2.P.7 of the CTD). The choice of materials for primary packaging should be justified. The discussion should describe studies performed to

demonstrate the integrity of the container and closure. A possible interaction between product and container or label should be considered. The choice of primary packaging materials should consider protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching), and safety of materials of construction.

Compatibility considerations

FDA Guidance for Industry Container Closure Systems for Packaging Human Drugs and Biologics highlights that packaging components that are compatible with a dosage form will not interact sufficiently to cause unacceptable changes in the quality of either the dosage form or the packaging component.5 The guideline present examples of interactions which include:

Loss of potency due to absorption or adsorption of the active drug substance

Degradation of the active drug substance induced by a chemical entity leached from a packaging component

Reduction in the concentration of an excipient due to absorption

Adsorption or leachable-induced degradation

Changes in drug product pH

Discoloration of either the dosage form or the packaging component

Increase in brittleness of the packaging component

Some interactions between a packaging component and dosage form will be detected during qualification studies on the container closure system and its components. Others may not show up except in the stability studies. Therefore, any change noted during a stability study that may be attributable to interaction between the dosage form and a packaging component should be investigated and appropriate action taken. Table 13-3 summarizes typical packaging suitability considerations for common classes of drug products.

Health Canada has also established the correlation of the parameters required to be checked to prove the suitability of the CCS.6 Table 13-4 summarizes typical packaging suitability submission considerations for common classes of drug products.

Submission Level Information

The data collected during the development of a preparation should be presented in the section on pharmaceutical development (3.2.P.2.4 Container Closure System) to justify the choice of the material(s) of construction in relation to the stability, integrity and

compatibility of the medicinal product, to the method of administration and to any sterilization procedures, if applicable. Specific information for plastic materials should include details on:

The compatibility of the plastic material with the medicinal product by performing extraction and interaction studies, where appropriate, and/or toxicological documentation, where applicable.

The influence of the manufacturing process of the medicinal product on the plastic material, where applicable (e.g., sterilization conditions)7

Leachables

USP-NF <1664> highlights that management of leachables is important to pharmaceutical product manufacturers and regulatory authorities because certain leachables above specific concentrations can present safety concerns for patients and/or

compatibility issues for drug product formulations.8 During the 1980s, the FDA began to formally and comprehensively address leachables in drug products after findings of patient sensitivity induced by leachables and other potential safety concerns related to leachables. Since then, management of both extractables and leachables for packaging systems and final drug products has become an important part of pharmaceutical development and regulatory submissions for many dosage form types, particularly for those deemed of relatively high risk for dosage form interaction with the packaging system, along with a relatively high safety risk based on the route of administration.

Remaining relatively high-risk dosage forms include: inhalation aerosols and solutions, injectables and injectable suspensions, ophthalmic, and transdermal ointments and patches. It is important to note, however, that even low-risk dosage forms present some risk and that appropriately rigorous leachables assessments can be important to particular drug products in lower risk dosage form categories (e.g., topicals and oral dosage forms, etc.) (Table 13-5).

Based on Current FDA Perspective on Leachable Impurities in Parenteral and Ophthalmic Drug products,9 leachables in ophthalmic and parenteral products:

Can originate from primary container closure

Can migrate through semi-permeable containers

Can originate from resins (including additives and base polymers), adhesives, inks, and secondary packaging

In terms of their nature and identity leachables can be:

Chemicals present in flexible plastic films and tubing

Printing inks (labeling stamped directly on containers)

Adhesive from labels

Overwrapping (flexible containers)

Elastomeric closures (rigid vials)

Components of glass (vials, bottles, syringes)

An illustrative presentation of the possible leachables from a plastic bottle intended for the packaging of a sterile solution is provided in Figure 13-4.9

Basic Considerations for Compatibility Studies

The European Medicines Agency (EMA) summarizes the basic points needed to be taken into consideration related to the compatibility studies strategy. There are two types: extraction and interaction.

The aim of extraction studies is to determine those additives of the material that might be extracted by the preparation or the active substance in contact with the material. Extraction studies are considered necessary for plastic material used for container closure systems of non-solid active substances and non-solid dosage forms for oral and topical (except ophthalmic) use if the material is neither described in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, nor has been approved for foodstuff packaging. For non-compendial plastic material used for container closure systems for non-solid medicinal products intended for inhalation, parenteral or ophthalmic administration, extraction studies are required even when approved for use in food packaging.

When evaluating the suitability of the selected plastic packaging material for the intended use, the compatibility of the material with the active substance or the medicinal product should be demonstrated. Testing may be performed by use of the plastic material, the plastic component, or the container itself. The extent and design of interaction studies depend on the physical state of the active substance and the dosage form of the medicinal product, respectively:

For solid active substances and solid dosage forms, the risk of interaction is low and generally does not require a content/container interaction study.

Solid dosage forms intended for inhalation or parenteral use, e.g., lyophilized products, may need interaction studies between the packaging material and the components of the formulation.

For non-solid active substances and liquid dosage forms, the risk of interaction requires comprehensive and suitable studies specific for each active substance/formulation.

The studies should evaluate the critical functional characteristics of the container/delivery system and should ensure that no significant alterations occur leading to a lesser quality of the active substance or the medicinal product. Interaction studies may include:

Migration studies to monitor the leaching of substances from the plastic material into the formulation/active substance, and/or

Sorption studies to evaluate a possible loss of drug quality due to adsorption or absorption effects.

Dissolution Development Considerations (for Solid Dosage Forms)

A dissolution procedure intended to be used as a routine control test for immediate release drug products should be robust, reproducible and discriminatory in order to assure a consistent product quality and to detect product quality attributes, which, if altered, may affect the in vivo performance.10 As such, a comprehensive development of the dissolution method should be included within the pharmaceutical development section. In principle, the following aspects should be considered in the context of this development study:

The dissolution characteristics of the drug product should be developed based on consideration of the pH solubility profile and pKa of the drug substance.

The selection of a suitable dissolution medium (composition, volume) should be based on the physico-chemical characteristics of the active substance(s) and the intended dose range of the drug product and the formulation to be tested. Based on FDA’s point of view, strict adherence to the gastrointestinal environment need not be used in routine dissolution testing. The testing conditions should be based on physico-chemical characteristics of the drug substance and the environmental conditions the dosage form might be exposed to after oral administration.

In general, an aqueous medium should be used and the pH should first be evaluated in the physiological pH range. In case of use of surfactants the concentration of the surfactant should be as low as possible and be justified by relevant solubility and dissolution data and an accompanying scientific discussion. As per ANVISA guidance RDC 31/2010 regarding selection of dissolution test conditions, it is noteworthy that demonstration that the concentration of the chosen surfactant is the lowest possible through the presentation of experimental data is of great relevance to prove the discriminative power of the dissolution method.

The selection of the dissolution apparatus is up to the applicant and should be sufficiently justified. The dissolution test methods most commonly used are (1) the basket method (Apparatus 1) and (2) the paddle method as generally recommended by EMA, FDA and ANVISA.

The development of methods using the paddle apparatus should start with a stirring speed of 50 rpm. Higher stirring speeds may be applied with an appropriate justification.

Based on FDA guidance, in general, mild agitation conditions should be maintained during dissolution testing to allow maximum discriminating power and to detect products with poor in vivo performance.

The development of methods using the basket apparatus should start with a stirring speed of 100 rpm. Higher stirring speeds or different basket mesh sizes may be applied with an appropriate justification. A higher stirring speed may be justified by high variability of the results observed at lower speed rates due to hydrodynamic effects (e.g., coning) or other factors (e.g., tablet sticking). However, it is known that methods with increased stirring speeds may be less discriminatory. Increasing the stirring speed at the expense of the discriminatory power simply to reduce variability of the results or to obtain complete dissolution in a shorter time should be avoided.

The discriminatory power should be discussed and demonstrated or otherwise justified. The FDA highlights that from a quality assurance point of view, a more discriminative dissolution method is preferred, because the test will indicate possible changes in the quality of the product before in vivo performance is affected.

Dissolution Control Considerations Among Various Health Authorities

Dissolution specification

The dissolution specification is expressed in terms of the quantity of active substance dissolved in a specified time, expressed as a percentage of the content stated on the product label.11 Dissolution testing and therefore dissolution drug product specifications are formulation- and drug-product-specific tests.

The expectations related to the dissolution specification per different representative competent health authorities is presented in Table 13-6.

FDA Approaches for Setting Dissolution Specifications for Generic Products The approaches for setting dissolution specifications for generic products fall into three categories, depending on whether an official compendial test for the drug product exists and on the nature of the dissolution test employed for the reference listed drug. All approved new drug products should meet current US Pharmacopeia (USP) dissolution test requirements, if they exist. The three categories are:

1USP Drug Product Dissolution Test Available: The quality control dissolution test is the test described in the USP.The Division of Bioequivalence, Office of Generic Drugs, also recommends taking a dissolution profile at 15-minute intervals or less using the USP method for test and reference products (12 units each).

2USP Drug Product Dissolution Test Not Available; Dissolution Test for Reference Listed NDA Drug Product Publicly Available: A dissolution profile at 15-minute intervals of test and reference products (12 units each) using the method approved for the reference listed product is recommended. The Division of Bioequivalence may also request submission of additional dissolution testing data as a condition of approval, when scientifically justified.

3USP Drug Product Dissolution Test Not Available; Dissolution Test for Reference Listed NDA Drug Product Not Publicly Available: Comparative dissolution testing using test and reference products under a variety of test conditions is recommended. In all cases, profiles should be generated as previously recommended. The dissolution specifications are set based on the available bioequivalence and other data.

Biowaiver Considerations

The biowaiver is an important tool for waiving the regulatory requirement for in vivo bioavailability (BA) and/or bioequivalence (BE) studies in both new and generic drug development and the relevant documentation which support this is proposed to be an integral part of the pharmaceutical development section, even if based on the dossier structure it can or must be described at different locations.

The advantages of applying it are the following:

Simplification of approval process reduction of development time and therefore overall product costs

Avoidance of unnecessary human testing 

There are three major biowaiver types:

Strength biowaiver

Biopharmaceutics classification system (BCS)-based biowaiver

Well-established use application

Strength Biowaiver

If several strengths of a test product are applied for, it may be sufficient to establish bioequivalence at only one or two strengths, depending on the proportionality in composition between the different strengths and other product-related issues described below.

The type or types of strength to evaluate depends on the linearity in pharmacokinetics of the active substance. If bioequivalence has been demonstrated at the strength(s) most sensitive to detect a potential difference between products, in vivo bioequivalence studies for the other strength(s) can be waived.

The following general requirements must be met to claim a waiver for additional strengths:

1The pharmaceutical products are manufactured by the same manufacturing process

2The qualitative composition of the different strengths is the same

3The composition of the strengths is quantitatively proportional, i.e., the ratio between the amount of each excipient to the amount of active substance(s) is the same for all strengths (for immediate release products coating components, capsule shell, color agents and flavors are not required to follow this rule); if there is some deviation from quantitatively proportional composition, condition c) is still considered fulfilled if condition i) and ii) or i) and iii) below apply to the strength used in the bioequivalence study and the strength(s) for which a waiver is considered:

a.The amount of the active substance(s) is less than 5% of the tablet core weight, the weight of the capsule content.

b.The amounts of the different core excipients or capsule content are the same for the concerned strengths and only the amount of active substance is changed.

c.The amount of a filler is changed to account for the change in amount of active substance. The amounts of other core excipients or capsule content should be the same for the concerned strengths.

4Appropriate in vitro dissolution data should confirm the adequacy of waiving additional in vivo bioequivalence testing.

BCS-based Biowaiver

BCS is a scientific framework for classifying drug substances into one of four classes (as presented in Table 13-7) based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, BCS considers several key factors governing the rate and extent of absorption from immediate release solid oral dosage forms:

A BCS-based biowaiver may apply for an immediate release drug product if:

The drug substance has been proven to exhibit high solubility and complete absorption (BCS class I); and

Either very rapid (>85% within 15 minutes) or similarly rapid (85% within 30 minutes) in vitro dissolution characteristics of the test and reference product has been demonstrated considering specific requirements; and

Excipients that might affect bioavailability are qualitatively and quantitatively the same. In general, the use of the same excipients in similar amounts is preferred (i.e., within ± 10% of the amount of excipient in the reference product or less).

A BCS-based biowaiver is also applicable for an immediate release drug product if:

The drug substance has been proven to exhibit high solubility and limited absorption (BCS class III); and

Very rapid (>85% within 15 min) in vitro dissolution of the test and reference product has been demonstrated considering specific requirements; and

Excipients that might affect bioavailability are qualitatively and quantitatively the same and other excipients are qualitatively the same and quantitatively very similar (i.e., within ± 10% of the amount of excipient in the reference product or less).

Well-established Use Application

According to Article 10a of Directive 2001/83/EC it is possible to replace results of pre-clinical and clinical trials by detailed references to published scientific literature (information available in the public domain) if it can be demonstrated that the active substances of a medicinal product have been in well-established medicinal use within the EU for at least 10 years, with recognized efficacy and an acceptable level of safety. The following criteria for the demonstration of such well-established use should be taken into account:

The time over which a substance has been used with regular application in patients; quantitative aspects of the use of the substance, considering the extent to which the substance has been used in practice, the extent of use on a geographical basis and the extent to which the use of the substance has been monitored by pharmacovigilance or other methods

The degree of scientific interest in the use of the substance (reflected in the published scientific literature) and the coherence of scientific assessments.

Biowaiver Considerations for Specific Dosage Forms

In principle waiver of BE studies for other than immediate release dosage forms can apply provided that specific conditions are met with special note to the possible excipient interactions that may have in vivo impact.

Considerations for specific dosage forms are

presented in Table 13-8, and Table 13-9 summarizes the feasibility of biowaiver acceptance per various dosage forms.

Route of Administration

Drugs are introduced into the body by several routes.14 They may be:

Taken by mouth (orally)

Given by injection into a vein (intravenously), into a muscle (intramuscularly) or beneath the skin (subcutaneously)

Placed under the tongue (sublingually) or between the gums and cheek (buccally)

Inserted in the rectum (rectally) or vagina (vaginally)

Placed in the eye (by the ocular route) or the ear (by the otic route)

Sprayed into the nose and absorbed through the nasal membranes (nasally)

Breathed into the lungs, usually through the mouth (by inhalation)

Applied to the skin (cutaneous) for a local (topical) or bodywide (systemic) effect

Delivered through the skin by a patch (transdermally) for a systemic effect

Each route has specific purposes, advantages, and disadvantages, as presented in Table 13-10.

Other Considerations for Multidose Presentation

The use of multiple dose unit drug dosage forms has proven that penetration of the container closure system may result in microbial contamination of the drug product. Microorganisms are able to proliferate at a rapid rate; therefore, if the drug product is

conducive to microbial growth the microbiological quality of the contaminated product may be diminished in a very short period of time. FDA strongly recommends that finished product storage conditions and related holding periods should be product-specific and supported by scientific data. Pharmaceutical companies should use a risk assessment approach to demonstrate that the preparation and storage conditions which are described in the product label do not put the final drug product at significant risk to be microbiologically unsafe to the patient. Table 13-11 lists some agency multidose presentation guidelines.

Conclusion

Pharmaceutical development is a complex multidisciplinary function critical to the successful development of any new medicinal product. Its purpose is to develop processes and methods for producing safe and effective drugs. The knowledge gained

from pharmaceutical development studies and manufacturing experience offer scientific understanding to support the establishment of the design space, specifications, and process controls.

A more systematic approach to development, defined as quality by design, can consider the incorporation of prior knowledge, results of studies using design of experiments, use of quality risk assessment, and use of knowledge management throughout the lifecycle of the product. Though often in the shadow of clinical development, pharmaceutical development drives important improvement, helping to accelerate drug development, pioneer cutting-edge pharmaceutical technologies, devise new pharmaceutical forms of drug delivery that make conditions “druggable,” optimize development cost, increase patient adherence, and broaden access for undertreated populations.