Social Aspects of Drug Discovery, Development and Commercialization Copyright © 2016 Elsevier Inc.
http://dx.doi.org/10.1016/B978-0-12-802220-7.00008-9 All rights reserved. 169
CHAPTER 8
Pharmaceutical Formulation and
of analytical methods, the process of manufacture and scale-up, new product transfers, infrastructure, and all the associated materials; production (includ- ing packaging and labeling), quality control, and assurance; and the process of distribution. In order to satisfy these manufacturing needs, all these steps have to conform to the applicable regulations to satisfy the ultimate regula- tory mandate of quality [1–4].
Chemistry, manufacturing and control refers to all the operations un- der pharmaceutical development, concerned with the drug substance and product that are critical to safety and delivery of accurate doses with the potency required for adequate therapeutic effect in the human system.
The first aspect of pharmaceutical manufacturing in the drug discovery lifecycle is research into the physical properties of the drug components for stability, compatibility, and other qualities that might influence for- mulation into the desired dosage forms. Complete understanding of the preformulation properties permit specific formulation to be designed and evaluated. In the manufacturing stage, the developing drug compound or new drug entity (NDE) becomes the active pharmaceutical ingredi- ent (API). First, the API is synthesized along with development of the procedure for the manufacturing process followed by formulation into a drug product. Chemical synthesis is a continuous process that parallels the NDE maturity across the development stage of the drug discovery program. The overall aim is to formulate API and excipients into a dosage form of interest based on medical indication, half-life, and frequency of need. Oral drugs are the most compliant and would be a first choice in pharmaceutical development. Oral drugs are usually formulated as sus- pensions, solutions, capsules, or tablets. Excipients that are acceptable by the US Food and Drug Administration (FDA) are known as “Generally Recognized As Safe” – the first priority in determining the right sub- stances to be used in formulations.
In the manufacturing stage, the extent of API supply is critical and re- quires significant quantities in order for development activities to begin.
Through scale-up, laboratory quantities are increased with special caution so as not to alter the original optimized properties. Sometimes other problems influence the ability to scale up from laboratory size to commercial size.
This is the reason for repeating production runs of the original synthesis, done in a manner to demonstrate reproducibility and to generate sufficient quantities with acceptable clinical standards. Limited and measured quanti- ties are dispatched for clinical trials, for package design, and for other appli- cation measures for technology transfer for scale-up and commercialization
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(Figure 7.1). All these activities are rooted in the International Conference on Harmonisation (ICH) guidelines that must be followed for the inves- tigational new drug (IND) to be deemed qualified to progress to the next stage (Figure 8.1).
8.2 REGULATORY ASPECTS OF PHARMACEUTICAL DEVELOPMENT
8.2.1 Overview
Federal regulations strictly control the processes that develop a new drug entity into a drug product to assure “the proper identification, quality, pu- rity and strength of the investigational drug.” This means the structure must be proven and kept consistent (identity); assay of the drug substance and drug product should demonstrate stability and potency that is devoid of impurity and degradates (quality), with adequate chemical and microbial purity; and strength of the investigational drug (purity) must be maintained.
In order to maintain the regulatory standards, the pharmaceutical industry adopts the culture of quality in all areas of drug manufacturing (Figure 7.2).
These demand proper accommodation of all the best practices, especially for manufacturing, good manufacturing practice (GMP); documentation, good documentation practices; and other related activities. GMP is a rudimentary aspect of the pharmaceutical quality system (PQS), which is binding for every drug manufacturer (Figure 8.2).
Figure 8.1 Product Formulation and Manufacturing Process.
In the manufacturing facility, there is control and consistency in all the operations from receiving of raw materials through to the release and distribution of final product. Systematic changes, both the anticipated and unanticipated, are handled with extreme caution. Only qualified personnel with specific expertise in the assigned roles are employed and must follow written procedures for all equipment used; the layout of the premises must be approved before pharmaceutical operations resume in such facilities.
Sterilization processes and cleaning processes must be validated, verified, and monitored continuously for changes. Collection of information, analy- sis, evaluation, implementation, and monitoring are carried out by trained personnel.
8.2.2 The International Conference on Harmonisation Technical Documents for Pharmaceutical Development
ICH was established in 1990 in a joint industry and regulatory endeavor to strengthen the efficiency of the process for developing and registering new drugs. Generally, ICH Q8, 9, and 10 are a combination of techni- cal requirements that must be strictly followed to cover all the processes involved in pharmaceutical development and manufacturing. ICH Q8 guidelines recommend the principles of Quality by Design (QbD), which means “building quality in” and “right at first time.” QbD must be adopted according to regulatory standards as outlined in the Q8 document. ICH Q9 is concerned with identifying risks and analysis, and also the potentials of risky events and evaluation activities involved in addressing these risks. It is expected that drug developers proactively address these issues by incor- porating risk assessment during product development to be able to clearly discriminate between critical and noncritical parameters and attributes.
ICH Q10 is a harmonized pharmaceutical quality system implemented throughout different stages of a product lifecycle. Application of Q10 is ex- pected to eliminate inconsistencies for robustness and effectiveness. While
Figure 8.2 A Crucial Need is That Safety, Efficacy and Quality will be Reproduced Throughout the Product Lifecycle.
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PQS covers the entire product lifecycle, the elements are applied vigor- ously to continually determine areas of future improvement, requiring a complete compliance to be based on application of the three most impor- tant ICH Qs, Q8, Q9, and Q10. These guidelines are harmonized among the concerned countries of which the major regulatory powers are the United States, Europe, and Japan.
A major requirement by the federal regulatory authorities is that all the information that supports the proposed manufacturing formulation process be submitted and contains all the information about the product that is critical to product quality. The Pharmaceutical Analytical Technology initia- tive was introduced by the FDA in 2004 to improve the production pro- cesses through implementation of new monitoring and control technology that could enhance the manufacturing processes. This has received wide recognition and acceptance by the industry and other regulatory authorities nationwide. Further discussions explore aspects of pharmaceutical develop- ment with factors that affect development productivity.
8.3 FORMULATION AND MANUFACTURING IN PHARMACEUTICAL DEVELOPMENT
The specific goal of the manufacturing program is to develop a drug that meets the regulatory acceptance criteria as shown in Table 8.1.
Table 8.1 Drug product specifications Attribute
Acceptance criteria (typical values)
Analytical procedure (for example)
Identity Matches standard IR or HPLC/UV
Appearance Color, imprint Visual
Assay 90–110% HPLC
Dose uniformity Statistical criterion (USP) HPLC or weight Release from dosage
form
80% in 15 or 30 min Stirred aqueous vessel Impurities (related
substances) <l% to few percent HPLC Microbial limits or
sterility
# of total aerobes and fungi per gram pathogen (–)
Growth in special media
Water content Few % Chemical or weight loss
Preservative content NLT 75% of initial HPLC
Source: Ref. [5].
8.3.1 Formulation Development
The physicochemical characteristics of the API are critical to formulation development. They enable identification of the stability status or any type of changes that may occur during the process. The preformulations are evaluated in terms of technical feasibility, dissolution behavior, stabil- ity, and maximum strength for further optimization. The stability studies are conducted under the long-term storage condition specifications (250˚C/60% RH), and are needed to obtain the registration data during the market phase (upon approval), and are performed by manufacturers for continuous quality check of products to ensure consistency in quality.
Stability provides evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light to recommend storage con- ditions. The results are used as the basis for defining the recommended storage conditions and the type of protection (e.g., packaging). Quantities in the range of hundreds of grams of drug substance are usually required [6]. The chemical development of drug substance is sensitive to changes in impurity profile for the various types of studies for which its use is directed.
These activities are usually completed within 1–2 years prior to resubmit- ting applications for New Drug Application/New Drug Submission. A vali- dated methodology is essential for testing the drug substance used in clinical manufacturing. Validation must demonstrate accuracy, precision, specificity, reproducibility, sensitivity, ruggedness, and linearity, conducted according to the ICH guidelines. The decision tree approach is needed to maximize the use of time in development and manufacture of drug formulations for the first-in-human oral dose [7]. Accurately documented information derived from the early formulation is utilized toward optimization and preparation for the scale-up and commercial quantities. These procedures require more rigorous analytical control assays and synthetic steps.
8.3.2 Manufacturing Development
The main objective of pharmaceutical manufacturing is continuous supply of API of consistent quality. The API process consists of a series of stages:
chemical transformations or purifications that may require isolated or non- isolated intermediates. These comprise numerous unit operations, which are executed according to set limits. They are concerned with the syn- thetic route selection for the drug substance and product, mechanism of API impurities formation, and the suitability of the optimization studies.
All activities are constantly monitored during the laboratory pilot scale to
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commercial scale. In-process testing cross-verifies a specific condition that has been achieved prior to the next step in the process [8]. It identifies the critical process parameters and control strategies for all of the individual steps, unit operations, and the ranges; in-process controls and specifications constitute the API process. Critical process parameters exist for each step or stage of the manufacturing process and are optimized according to require- ments. These are executed according to ICH Q11.Validated test methods are used to detect differences in stability, content, and purity of the API in the clinical samples to be included in the submission dossier for IND.