Impact of Pharmaceutical Product Quality on Clinical Efficacy

C H A P T E R

21 Impact of Pharmaceutical Product Quality on Clinical Efficacy Vandana Soni1, Vikas Pandey1, Saket Asati1 and Rakesh K. Tekade2,3 1

Department of Pharmaceutical Sciences, Dr. H.S. Gour Central University, Sagar, Madhya Pradesh, India 2Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia 3National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India O U T L I N E 21.1 Introduction 21.2 Risk Assessment and Management of Medicine 21.2.1 Product Quality Defects 21.2.2 Medication Errors 21.2.3 Known Side Effects 21.3 Elements of Pharmaceutical Development 21.3.1 Quality Target Product Profile 21.3.2 Critical Quality Attributes 21.3.3 Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs

Dosage Form Design Considerations DOI: https://doi.org/10.1016/B978-0-12-814423-7.00021-6

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21.3.4 Design Space and Control Strategy

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21.4 Factors Affecting Drug Product Performance 748 21.4.1 Physicochemical Properties of Drug Substance 748 21.4.2 Differences in Manufacturing Processes 752 21.4.3 Differences in Excipients, Excipient Selection, and Quality Control 754 21.5 Drug Product Quality and Drug Product Performance

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21.6 Scale-Up and Postapproval Changes

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© 2018 Elsevier Inc. All rights reserved.

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21.6.1 FDA Level of Changes 21.6.2 Assessment of the Effects of the Changes 21.6.3 Critical Manufacturing Variables 21.6.4 Bulk Active Postapproval Changes 21.7 Postmarketing Surveillance

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21.8 Conclusion

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Acknowledgment

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Abbreviations

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References

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Further Reading

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21.1 INTRODUCTION The quality of a pharmaceutical product is the major criterion for the better clinical efficacy in the human body. The quality of pharmaceutical product development is a vital part for the different regulatory authorities and the pharmaceutical industry to meet the requirement of the swift growing demand. To maintain the quality of pharmaceutical product, there is the requirement for the suitable processes, pharmaceutical tests, and apparatus. The following advantages are important which are accomplished by proper development of a pharmaceutical product (Pramod et al., 2016): • • • •

successful product development; subsequent rapid regulatory approval; reduce extensive validation load; considerably lessen postapproval changes.

Product safety is the main criterion focused by all regulatory agencies as well as drug manufacturers. The formed product should be safe and effective to establish standards of quality and should be manufactured according to current Good Manufacturing Practices (cGMPs) requirements. The entire batches of drug products released by a company must follow the standards and specifications along with the company requirements. Failure in these specifications of a marketed drug product must be recorded and reported to the regulatory agencies for their immediate corrective and preventive measures (Patel and Chotai, 2011). Various parameters affect the product quality in the manufacturing industries. In the 21st century, the Food and Drug Administration’s (FDA) primary objective is to encourage a high-quality product with the help of competent, active, and high quality manufacturing technologies in the pharmaceutical industry (FDA, 2004). The product quality has been enhanced with the better understanding of cGMPs, process analytical technology, and quality by design (QbD) approaches. There have been disputes regarding the increase in drug recalls and shortages which show the failure of the product quality in pharmaceutical industry over the same period (Nagaich and Sadhna, 2015).

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Most of the pharmaceutical drug product shortages and their recalls may be due to poor product quality during the product fabrication process (FDA, 2013). These types of recall and shortages of the pharmaceutical product are responsible for the long-term improvement of the industrial parameters which are needed for the development of a high-quality drug product. Therefore, the industries are continuously trying to enhance the product quality for the manufacturing of better and safer drug products. A highquality product is principally related to safety and efficacy, thus, it must be ensured that the drug product has suitable quality standards or specifications during the manufacturing process. The different regulatory agencies are regularizing the manufacturing industries to make high-quality product because the consumers or patients are unaware about product quality until they face any serious problem related to the product (Stegemann, 2016). The pharmaceuticals have a direct impact on the human body. Thus, their regulation is very essential for the purpose of safety. The quality of products should show better performance with a high level of safety. So, the manufacturers are trying to develop high-quality products with regard to the clinical efficacy and safety of the drug product. The manufacturers have only a few economic benefits related to the quality. The FDA needs to simplify their regulatory requirements related to the manufacturing, so that the manufacturers can get the higher economic incentive (Woodcock and Wosinska, 2013). For the development of a high-quality product, various methods have been utilized. The identification and determination of different sources of risk from medicine and pharmaceutical development techniques are very useful for the development of quality product. There are various risk factors which affect the quality of the product. They include product quality defects, medication errors, and known side effects. These factors should be identified and corrected prior to the product development so as to improve the quality of product. The QbD is one of the most common approaches commonly used for the optimization and manufacturing of high-quality products. The design includes various quality related parameters like quality target product profile (QTPP), critical quality attributes (CQAs), risk assessment of factors, and elements associated with the QbD (Sangshetti et al., 2017). From the beginning of the 21st century, various initiatives have been taken for the improvement of the product quality with the modernization of technology and equipment used in the manufacturing processes. These initiatives help in the acceptance of modern techniques by the following steps: Set up the relationship between public and private research institutions; Advancement in manufacturing process regulations; Maintain drug quality standards; Provide good funding for the new and safe technology in the field of manufacturing of quality product; 5. Maintain the harmonization of emerging and new technology throughout the world and provide wider and broader applicability of these techniques, which can be used globally (O’Connor et al., 2016). 1. 2. 3. 4.

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21.2 RISK ASSESSMENT AND MANAGEMENT OF MEDICINE There are various risk factors which affect the clinical efficacy of the product. These risk factors are associated with the product quality defects, medication administration errors, and adverse drug reactions (ADRs) or known side effects. These risk sources are the major factors which affect the clinical safety and efficacy of the product. The marketed products that are used in hospitals or general practices may not show the same effect as they showed in the clinical trial study (Poeran et al., 2014; Naci and Ioannidis, 2015). This difference in the effect may be due to the fact that in a clinical trial study, only a few numbers of patients use the medicine for a short period, but when studies are carried out in large populations, some ADRs may be observed. Thus, the complete safety and effectiveness of the product can be predicted by determining product’s overall marketing life and their recalls from the market (Eichler et al., 2011). To consider these effects, a branch called pharmacovigilance plays an important role. It is the branch of pharmacy that deals with the safety and efficacy of the drugs from the research time to their marketed period; hence, it determines and includes all the risk factors associated with the drug during clinical studies. There are various steps undertaken for pharmacovigilance purposes, like determining the unknown side effects of drugs of daily use, evaluating their effects with risk factors, and fixing the effective and safe dose of the drugs to the patient (Edwards and Bencheikh, 2016). The drug is believed to be safe when it is expected to show greater effects than the adverse effects or risks associated with them. The quality of the product should be maintained throughout the storage period, and remain constant in all respects when it is used in order to minimize the product recalls and shortage from the market. Some of the sources of risks from medicine are discussed below:

21.2.1 Product Quality Defects The product quality, safety, and efficacy are affected by several undesirable factors which are present in the product itself and responsible for the product or quality defects (Lipsitz et al., 2016). Most of the product recalls, and reduction in supply may be due to these quality defects. Therefore, the sources of the quality defects need to be identified (Kweder and Dill, 2013; Ebbers et al., 2016) and reported to the manufacturer and regulatory authority, so that the necessary actions can be taken for the protection of human health from the suspicious medicines. Various authorities have been appointed for the detection of these product quality defects. The health product quality regulatory authority quality defects and recall group or FDA are the authorities for the product quality management system and maintain the product quality as per the guidelines (HPRA, 2017). The severity of the medicinal products on the human health, and hence the product quality defects or recalls may be classified into three types (FDA, 2017):

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21.2.1.1 Critical Quality Defects or Class I Recall These defects may lead to very dangerous and life-threatening effects which will cause death or other serious permanent damage to the human body. The defects are responsible for the class I recall of the product from the market. For example, defective artificial heart valve, defective catheter, incorrect information of dose strength, dosing information, etc. (FDA, 2017; HSA, 2017). 21.2.1.2 Major Quality Defects or Class II Recall These defects may be responsible for the temporary damage or illness to the human body, which are reversible. Thus, these lead to the class II recall of the product. For example, contamination in medical device and package defects (FDA, 2017). 21.2.1.3 Minor Quality Defects or Class III Recall These defects are not very harmful to human health and do not have any adverse effect consequences. Class III recalls may be used for these types of defects. For example, in 2010 children’s medicines were contaminated with plastic materials and thus were recalled from the market (http://www.alllaw.com/articles/nolo/personal-injury/fda-class-i-ii-iiirecalls.html). Some of the product recalls with their appropriate reasons and manufacturers are given in Table 21.1.

21.2.2 Medication Errors Medication errors are general and can cause appreciably harm to patients. Medication errors are caused by incorporating wrong and inaccurate doses in the product development which cause discomfort leading to severe problems for patients. Medication errors may be defined as the failure in the treatment of any disease which may cause either preventable adverse effects or serious effects leading to death or permanent injury to the patient or consumers (Aronson, 2009). The word failure means the effect of the medication is not up to the standard level, which has been set up previously by some experiments. These errors are present due to various reasons, like prescription errors, dispensing of the formulation, administration, product name, labeling, packaging, miscommunication, monitoring failure, etc. (Mohammadi et al., 2015). The medication errors may lead to different adverse effects on the human being. The adverse effects are defined as the any abnormal or unplanned effects of the medicine that could be responsible for the ADRs. An ADR is the objectionable and harmful reaction which influences the safety and efficacy of a medication and/or drug product (Alomar, 2014). Some medication errors may also cause an adverse event that is not classified under the category of ADRs, e.g., when a cannula penetrates a blood vessel causing temporary swelling of a blood vessel, known as hepatoma. One incident of ADR of medication errors happened in 1985: some patients, mostly children, were seriously affected with spinal injections that contained harmful vinca alkaloids that lead to paralysis or death of some of the patients (Arcangelo and Peterson, 2006). Therefore, medication errors are not always responsible for causing serious adverse reactions, but sometimes these errors may be free

DOSAGE FORM DESIGN CONSIDERATIONS

TABLE 21.1

List of Products Recalled With Their Associated Reasons

Product Brand Name With Description

Types of Recalling

Manufacturer

Country Reasons/Defects

Official Recall Date

All unexpired sterile drug syringes and IV bags

Voluntary (hospital and user level)

Cantrell Drug Company

USA

Lack of sterility assurance

25-07-2017

Ultra-Sten capsules (dietary supplement)

Voluntary (consumer level)

Hardcore Formulations

USA

05-07-2017 Presence of unapproved drugs (Methylstenbolone, an anabolic steroid)

Serious liver injury, Increased risk of heart attack and stroke, kidney injury, etc.

D-Zine capsules (dietary supplement)

Voluntary (consumer level)

Hardcore Formulations

USA

Presence of unapproved drugs (Dymethazine, an anabolic steroid)

05-07-2017

Serious liver injury, Increased risk of heart attack and stroke, kidney injury, etc.

Succinylcholine chloride 20 mg/mL

Voluntary (hospital/clinic level)

Fagron Sterile Services

USA

Short of sterility assurance and presence of microbial growth

23-06-2017

Systemic invasive mycoses and systemic bacterial sepsis

Eliquis (apixaban) 5 mg Tablets

Voluntary (consumer level)

Bristol-Myers Squibb

USA

Tablet Mix-Up (Bottle labeled as Eliquis 5 mg was found to contain Eliquis 2.5 mg tablets)

10-06-2017

Increased probability of stroke, blood clot and pulmonary embolism

Clindamycin Injection USP

Voluntary (hospital/retail level)

Alvogen

South Korea

Lack of sterility assurance and presence of microbial growth

16-06-2017

Systemic invasive mycoses and systemic bacterial sepsis

Nitroglycerin products

Voluntary (hospital/user level)

Advanced Pharma, Inc. d/b/a Avella of Houston

USA

Potential problem with 15-06-2017 product potency (lower than expected potency)

Interruption in patient’s treatment

Paliperidone ExtendedRelease Tablets, 3 mg

Voluntary (consumer/user level)

Teva Pharmaceuticals, Inc.

USA

Failed dissolution test 31-05-2017 causing less drug absorption

Treatment failure

Tetracycline-ABC and Dibecline topical products

Voluntary (retail level)

Phillips Company

USA

Due to incorrect processing procedure

14-06-2017

Affect safety and efficacy of the product posing a risk to patients

BRILINTA (ticagrelor) 90 mg tablets

Voluntary (physician and consumer level)

AstraZeneca

UK

Mixing of BRILINTA (ticagrelor) and ZURAMPIC (Lesinurad)

25-05-2017

Acute renal failure, risk of heart attack and stroke

Lupin Pharmaceuticals Inc.

USA

Out of sequence tablets and Expiry/Lot information was not printed on the package

25-05-2017

Risk of contraceptive failure and unintended pregnancy

Mibelas 24 Fe (Norethindrone Voluntary Acetate and Ethinyl Estradiol (consumer level) 1 mg/0.02 mg chewable and ferrous fumarate 75 mg) Oral contraceptive

Risk Statements Serious life-threatening infections

Amitriptyline HCl Tablets, Voluntary USP 50 mg and Phenobarbital (consumer/user Tablets, USP 15, 30, 60, level) 100 mg

C.O. Truxton, Inc.

USA

Lack of proper labeling

08-05-2017

Overdose of Amitryptiline may cause uneven heartbeats, extreme drowsiness, seizures, etc. Overdose of Phenobarbital may cause cardigenic shock, coma, renal failure, etc.

25% Dextrose Injection, USP (Infant)

Voluntary (hospital/user level)

Hospira, Inc.

USA

Presence of particulate matter (human hair)

Baby teething tablets and Nighttime teething tablets

Voluntary (consumer level)

Standard Homeopathic Company

USA

Contains variable amounts 13-04-2017 of belladonna alkaloids from the calculated amounts

Serious health hazard

Multiple compounded sterile products

Voluntary (hospital/user level)

Isomeric Pharmacy Solutions

USA

Possible lack of sterility

06-04-2017

Systemic invasive mycoses and systemic bacterial sepsis

EpiPen (epinephrine injection, Voluntary USP) and EpiPen Jr (epinephrine injection, USP) Auto-Injectors

Mylan N.V.

USA

Failure to activate the device 31-03-2017 due to a potential defect

Significant health consequences

All unexpired sterile injectable products labeled “latex free”

Voluntary (user level)

Avella Specialty Pharmacy

USA

Products may contain synthetic latex and natural latex

23-02-2017

Allergy, swelling, and inflammation

Ibuprofen Lysine Injection, (20 mg/2 mL)

Voluntary (hospital/user level)

Exela Pharma Sciences, LLC

USA

Found to contain particulate matter

08-02-2017

Blood vessel blockage, provoke immune response, microinfarcts lead to lifethreatening side effect

Duravet (Duramycin-10 Soluble Powder)

Voluntary (consumer level)

Huvepharma, Inc

Bulgaria Possible undetermined hazard

28-12-2016

Significant health consequences

Megajex; Tadalafil and Sildenafil capsules (Male Sex Enhancer Dietary Supplement)

Voluntary

MS Bionic, Inc

USA

29-11-2016

May cause lowered blood pressure to the dangerous level

Unapproved new drug

21-04-2017

Local swelling, blockage of blood vessels and systemic allergic response

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FIGURE 21.1

21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY

Venn diagram illustrating the relationship between medication errors and ADRs and adverse events.

from any type of adverse events. The Venn diagram in Fig. 21.1 shows the relationship between medication errors and adverse events (Ferner and Aronson, 2006). 21.2.2.1 Classification of Medication Errors The medication errors may present due to mistakes that occur in the planning and processing during the manufacturing and dispensing time. These errors can be broadly categorized as mistakes and skill-based errors. Then, these errors may be further classified into the four classes, i.e., action-based errors, knowledge-based errors, memory-based errors, and rule-based errors. The knowledge-based errors and rule-based errors are categorized into the mistakes class while action-based errors and memory-based errors fall under the skill-based category (Aronson, 2009). 1. Knowledge-based errors: These errors are present due to lack of complete knowledge about the medication, e.g., when penicillin is given to an allergic patient without prior knowledge about the patient history. Communication problems between the health professionals and consumers that may lead to misinterpretations in the drug dosing and dispensing of the medication can fall under this category (Evans and Swan, 2015). These errors can be minimized by providing the full knowledge about the medication to the consumers. Some other methods or technologies, like, computer- and bar-coded prescription system and cross-verification of prescriptions by health professionals, can also reduce the errors (Keers et al., 2013). 2. Rule-based errors: Two types of medication rules, i.e., good rules and bad rules, are available. When bad rules are applied, or good rules are misapplied or not applied, rulebased errors are present, e.g., diclofenac injection injected into the thigh muscle instead of buttock leads to intense pain. Therefore, good rules and better knowledge reduce these types of errors (Kim, 2011; Keers et al., 2013). DOSAGE FORM DESIGN CONSIDERATIONS

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3. Action-based errors: These are the technical type errors. Wrong labeling on the drug product or misinterpretation in reading of a prescription may lead to action-based errors e.g., diltiazem is given in place diazepam due to misreading of labels. This error may lead to serious harmful effects on the human being due to administration of an inappropriate medicine (Grissinger, 2012). These errors can be reduced with proper labeling and prescribing the medication in the correct format (Filik et al., 2006). 4. Memory-based errors: The errors are present due to forgetting about the proper dose, or allergic or harmful drugs are prescribed, e.g., forgetting the allergic reaction of a patient to penicillin. The errors can be minimized with the help of the computer-based prescription system, in which the patient history is saved, including all the allergic reactions (Macy, 2014). All these errors can occur due to various factors that depend upon the working conditions of the individual. For example, increased medication errors by the nursing staff and doctors due to poor support, depression, overtime working with insufficient resources, and job security stress. The errors are minimized through proper knowledge and improvement of working conditions of the health professional staff (Shanafelt et al., 2002; Fahrenkopf et al., 2008; Wilkins and Shields, 2008).

21.2.3 Known Side Effects The major function of the FDA is to approve the safety and efficacy of drugs to be sold in the US market. Drugs are to be considered safe when they show high efficacy with lowrisk factors or side effects. Side effects (adverse events) are the unwanted signs and symptoms due to medicaments or drug products during the treatment (Kuhn et al., 2015). Various factors which affect the intensity and incidence of side effects depend upon the gender, age, individual pharmacokinetic parameters, races, metabolic enzyme activity, etc. It may be noted that some side effects may happen when: • The new drug is administered as the complementary medicines; or • Withdrawal of some drugs may lead to side effects like withdrawal syndromes; or • Increasing or decreasing the dose amount for long-term medicines. All medicines and drug products are responsible for some common side effects. These drug products cover all types of medicines like prescription or over-the-counter (OTC) drugs, vitamins, herbal preparations, etc. For example, β-lactam antibiotics, like penicillin, and other antibiotics, and other drugs like sulfonamides, cause allergic reactions and skin rashes in the majority of the population (Kuyucu et al., 2014). Complementary medicines are the medicines which are given along with the standard or primary treatment, like herbal medicines, vitamins. These herbal medicines or vitamin preparations may also be responsible for the side effects (Shirzad and Nasri, 2014). Some side effects of the prescription, OTC, or complementary medicines are given in Table 21.2. The side effects may be present in the range of mild to very serious effects. Some critical side effects lead to hospitalization or in some cases death may also occur. The side effects may also be responsible for some allergic or anaphylactic reactions. In an analysis from 1992 to 2012 in the United Kingdom, there was an increase in the anaphylaxis-related hospitalization cases due to the drug or food allergic reactions (Turner et al., 2015). Therefore, it DOSAGE FORM DESIGN CONSIDERATIONS

TABLE 21.2 List of Drugs and Their Reported Side Effects Disease Category

First-Line Drugs

Leading Brand Name

Reported Side Effects

Reference

Cancer

Imatinib mesylate

Glivec (Novartis, India)

Muscle cramps and bone pain, hypophosphatemia

Caldemeyer et al. (2016)

Imalek (Sun Pharma) Lupinib (Lupin) Cetuximab

Erbitux (Eli Lilly and Company)

Sore throat, weight loss, cutaneous side effect

Vinod and Diaz (2015)

Bevacizumab

Avastin (Roche)

Jaw pain, gum infection, age-related macular degeneration

Schmid et al. (2014)

Pemetrexed

Alimta (Eli Lilly and Company)

Anemia, myelosuppression, hepatotoxicity

Zattera et al. (2017)

Pemanat (Natco) Pemex (United Biotech) Rituximab

Ikgdar (Emcure) Mabthera (Roche), Reditux (Dr. Reddy’s)

Myelosuppression, inflammatory syndrome (tumor flare)

Ruan et al. (2015)

5-Fluorouracil (5-FU)

5-Flucel (Celon)

Leukopenia, diarrhea, stomatitis, and nausea

Focaccetti et al. (2015)

Idarubicin

Zavedos (Pharmacia)

Cardiovascular side effect, testicular damage

Langer (2014), Deihimi et al. (2017)

Vincristine

Alcrist (Alkem) Biocristin (Biochem)

Motor delay, bacteremia with anemia, peripheral neuropathy

Wang et al. (2016)

Aceten (Wockhardt), Angiopril-DU (Torrent), Capotril (Lupin)

Cardiac side effects, dry mouth, elevation of creatinine level

Zaher et al. (2016)

Atenolol

A-Card (Race Pharma), Abiten (Alpic Biotech), Acord Plus (Invision)

Hypotension, sleep disturbance, cold extremities

Raphael et al. (2016)

Timolol

Brimolol (Sun Pharma), Ganfort (Allergan)

Chest pain, cardiac arrest, cerebral ischemia, asthenia, respiratory problems

Raphael et al. (2016)

Dizziness, abnormal weight gain, stomach cramps, diarrhea

Angelakis et al. (2014), Srinivasa et al. (2017)

Hypertension Captopril

Bone-related disorders

Adrucil (Sun Pharma)

Hydroxychloroquine Arthoquin (Acekinetic), Hcqs (IPCA) Methotrexate

Alltrex (Miracalus), Biotrexate (Biochem), Mucosal, hematologic, hepatic and Caditrex (Cadila) gastrointestinal side effects

Shea et al. (2014)

Malaria

Sulfasalazine

Iwata (Cadila), Saaz (IPCA), Salazar-DS (Zydus)

Blood dyscrasias, Yellowing of skin and eyes

Chester Wasko et al. (2016)

Alendronate

Denfos (Dr. Reddy’s), Alenost (Macleods)

Atypical femoral fractures (AFF) and Osteonecrosis of the jaw (ONJ)

Ishtiaq et al. (2015)

Chloroquine

Cadiquin (Zydus Cadila)

Gastrointestinal intolerance, aquagenic pruritus, retinal toxicity, blurred vision, paresthesia, insomnia, “stings” into the skin

Goodman et al. (2001), Costedoat-Chalumeau et al. (2015), Martins et al. (2015)

Brainstem neurotoxic encephalopathy, bone marrow suppression, nausea, vomiting, anorexia, and dizziness, mild blood abnormalities

Ho et al. (2014), Lai et al. (2014)

Aralen Maliago (Cipla) Artemisinin

Alaxin (GVS Labs) Arte Plus (Zydus Cadila) Combither (Aristo)

Atovaquoneproguanil

Malarone (GlaxoSmithKline)

Stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)

WHO (2015), CDC (2017)

Quinine

Qualaquin

Tinnitus, slight impairment of hearing, headache, hypoglycemia, asthma, thrombocytopenia, hepatic injury, and psychosis

Achan et al. (2011)

Hepatotoxicity, neurotoxicity, Peripheral neuropathy, Lupus-like syndrome

Jnawali and Ryoo (2013), WHO (2010), Falzon et al. (2017)

Gastrointestinal upset, hepatotoxicity, exanthema, immunological reactions

Jnawali and Ryoo (2013), Falzon et al. (2017)

Hypersensitivity reactions, gastrointestinal upset

Jnawali and Ryoo (2013), Falzon et al. (2017)

Dizziness, blurred vision, color blindness, nausea, vomiting, stomach pain, loss of appetite, headache, rash, itching, breathlessness, swelling of the face, lips or eyes

Jnawali and Ryoo (2013), Falzon et al. (2017)

Cinkona (IPCA) Qinarsol (Cipla) Tuberculosis

Isoniazid

ISOKIN (Pfizer - Warner) CX-3 (Zydus- Cadila)

Rifampin

RIMACTANE (Novartis) CX-3 (Zydus- Cadila)

Pyrazinamide

Ethambutol

P-ZIDE (Cadila)

(Continued)

TABLE 21.2 (Continued) Disease Category

Diabetes

First-Line Drugs

Leading Brand Name

Reported Side Effects

Reference

Streptomycin

AMBISTRYN-S INJ (Sarabhai)

Ototoxicity, nephrotoxicity, vestibular dysfunction

Jnawali and Ryoo (2013), Falzon et al. (2017)

Metformin (I Line)

Gluconorm-SR (Lupin)

Gastrointestinal side effects, slow/irregular Raz (2013), Abdulheartbeat, stomach pain with nausea, Ghani et al. (2017) vomiting, or diarrhea

Glumet (Cipla) Insulin (II Line)

Bovine Fastact (USV) Humalog (Eli Lily)

Sulfonylureas (II Line)

Glimepiride (Amaryl) Glyburide (DiaBeta; Micronase)

Hypoglycemia, fast heartbeat, fainting, or seizure, sudden sweating

Abdul-Ghani et al. (2017)

Hypoglycemia, gastrointestinal upset, weight gain

Karagiannis et al. (2012), Sola et al. (2015), Abdul-Ghani et al. (2017)

Sore throat, muscle pain, weight gain, tooth problems

Abdul-Ghani et al. (2017)

Glipizide (Glucotrol) Glitazones (III Line)

Pioglitazone (Actos) Rosiglitazone (Avandia)

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becomes necessary to take medicines carefully under the supervision of medical professionals. There are some steps which could be helpful in the duration of any adverse event or before drug administration and thus can reduce the risk of experiencing the side effects. These steps may be as follows: • Asking for the prescribing information about the drug, so that the written side effect can be understood carefully before taking the medicine. For example, taking a nasal decongestant by a person suffering from hypertension would lead to unwanted reactions (FDA, 2017). • If any information is written on the label or packing of the container it needs to be read very carefully. The information may contain the proper administrative procedure or possible side effects. For example, store in a cool place, shake the bottle, do not use after a certain date, discard 28 days after opening, for topical use only, etc. • If any side effects are present after the administration of the drug, there is a need to seek the help from health professionals, so that he or she can suggest the correct remedy for the side effects. For example, during chemotherapy the proper diagnosis should be performed for the normal functioning of liver, if not so further treatment may be unsuitable unless the liver recovers (Sharma et al., 2014).

21.3 ELEMENTS OF PHARMACEUTICAL DEVELOPMENT The elements of pharmaceutical development are used to design and develop a product which would maintain the quality to show better performance of the drug. This could be achieved by gathering the information and knowledge from the scientific understanding and then incorporating them in research. The principle of pharmaceutical development is to develop an efficient manufacturing process for designing high-quality product. QbD is a systematic approach for the development of a pharmaceutical product which tries to meet the predefined quality standard of the product with high clinical efficacy. The QbD concept was first used and reviewed by Joseph Moses Juran. The QbD helps to understand risk factors with the scientific and hands-on techniques to enhance the drug product quality. The International Conference on Harmonization (ICH) has also approved these methods for the pharmaceutical development, pharmaceutical quality system, and quality risk management under the ICH Q8, ICH Q9, and ICH Q10 sections, respectively (FDA, 2006, 2009a,b). QbD techniques are based on the identification of CQAs which are required for the development and manufacturing of good quality product. The CQAs are the factors which select the appropriate critical process parameters (CPPs) by using QbD methods on the basis of their efficacy. These selected CPPs are helpful in the development of effective, robust, and flexible methods to produce high-quality product for the long duration of time (Lawrence et al., 2014). QbD-based approaches function as major processes for running any pharmaceutical industry effectively as these methods are related to developing a safe and effective product. There are various advantages of QbD methods, which are given below (Sangshetti et al., 2017); • Safety and efficacy of the products to the patient and consumers.

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• The method develops an effective, flexible, and robust process for better designing of the product. • Various CPPs and material attributes are optimized with scientific knowledge. • Risk assessments of the various factors may be done by providing better solutions to problems. • The developed product with QbD technique shows predefined quality standard and uniformity during the manufacturing process. • The design also reduces the cost of the product during scale-up and postapproval changes (SUPAC). The pharmaceutical developmental stage may follow different steps or elements of QbD techniques: • Step-I: The targeted product profile will be chosen and well defined on the basis of safety, use, and efficacy of the product. • Step-II: The risk factors will be indicated which affect the product quality and are related to the drugs, excipients, and other ingredients used in the formulation. • Step-III: The CQAs and CPPs will be selected with the help of various experimental works to optimize the product quality and efficacy. • Step-IV: The manufacturing method will also be developed by designing and changing the strategy and leads to product quality improvement.

21.3.1 Quality Target Product Profile The predefined standards of product quality, which should be followed during the manufacturing and optimization process, are considered to be the target product profile. When QbD methods are used to fulfill the targeted profile of the product then they are known as the QTPP. The QTPP is very important for the development of an optimized process. It also helps in the development of product having high-quality and efficacy with the help of CQAs, such as drug and dosage form characteristics, in the product development process (Lawrence and Kopcha, 2017; Sangshetti et al., 2017). ICH guidelines define the quality product profile under the section of ICH Q8 R2 on the grounds of designing and development of high-quality product. Factors influencing the quality target profile of the product are given below: • Route of administration, dose strength, and type of dosage forms, e.g., drugs which are degraded by acidic medium should not be administered by oral route or if administered they must be in a modified form, such as a coating concept can be used for maintaining their efficacy. • Drug release kinetics from the dosage form and their pharmacokinetic parameters such as modified-release drug products includes extended or modified release of active moiety. • Drug excipients interaction may be physical (between primary amine drugs and microcrystalline cellulose) and chemical (primary and secondary amines interact with reducing sugars) and may change the original form of the drug to affect its quality and efficacy.

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• Product purity, sterility, stability, and dosage form appearance. • Pharmacological and therapeutic effects produced by the drug from the final drug product.

21.3.2 Critical Quality Attributes CQAs are defined under the ICH Q8 R2 guidelines as, “physical, chemical, microbiological or biological properties which should be required within the certain range or limit to confirm the predefined quality standard product”. They are considered to be foremost factors for the development of any dosage form while maintaining quality. If variations are present in the range of these attributes, they show low or no risk to the quality of the product. The CQAs depend upon the type of dosage forms, drug substances, and excipients used in the formulation (Lawrence et al., 2014). For example, a controlled drug release formulation strongly depends upon the dissolution test; hence, it is a critical parameter for these formulations, while a dissolution test is not critical for an immediate drug release formulation due to high solubility of the drug (Sangshetti et al., 2017). The drug substance and excipients are used as raw materials for the manufacturing of any dosage form. The quality and quantity of these substances are referred to as the main attributes for the product development. CQAs may be different for the different formulations, e.g., dose strength, purity, release kinetics, and product stability are the main factors which affect the CQAs for the solid oral dosage forms. Similarly, the sterility and clarity are the major parameters for the parenteral dosage forms. The CQAs are obtained from the QTPP with the

FIGURE 21.2 Example of CQAs for nanoparticle preparation.

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prior knowledge about various attributes for the development of optimized process and product. Along with the materials attributes of the drug and excipients, some process parameters also strongly affect the CQAs, these parameters are known as CPPs (Lawrence et al., 2014). These CPPs may include operating conditions (like stirring speed, sonication time, temperature, pH), method of preparation, batch size, equipment type, and environmental factors (like moisture, aseptic condition). For example, nanoparticles formulation method may depend upon the various material attributes and process parameters and may be categorized as the CQAs, as shown in Fig. 21.2 (Li et al., 2017). Thus, the main objective of QbD method is to identify and define CQAs with the appropriate material attributes and CPPs. Process capability is a statistical term for the measurement of process robustness and reproducibility. Robustness means the consistency of product quality and performance with the tolerable limits of process variables. The most common formula for the process capability is six standard deviation approaches. The process capability index (CpK) is the ratio of tolerable limit of any character and the six sigma, i.e., process capability. The CpK formula is given below (Roy, 2012); CpK 5

Upper limit of specification 2 Lower limit of specification 6 Standard deviation

If the value of CpK is more than 1, then the process is robust and reproducible, hence, it is said to be a capable process (Glodek et al., 2006; Roy, 2012).

21.3.3 Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs The CQAs cover both material attributes and process parameters. The design space defines the relationship or connection between CQAs and CPPs. The design space is the region where the predefined standard quality product may be produced by using these linkage relationships. Hence, design space provides the region for the development of a

FIGURE 21.3

Relationship between the knowledge space, design space, and operating range.

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high efficacy quality product with the help of optimized process and prevents the product failure loss during the manufacturing process (Kelley et al., 2016). The knowledge space is a broad region, which includes all the critical and noncritical parameters during the process of product development. This region has critical attributes, which cover the design space and operating ranges, where the products are produced within a range of certain quality attributes maintaining quality for their effectiveness. Knowledge space provides the specific area of research in the field of product development, beyond the boundary of that there is no requirement of research (Kelley et al., 2016). Fig. 21.3 explains the relationship between the knowledge space, design space, and operating ranges of product development. Risk assessment is the method to determine the CQAs associated with the process and quality of product. The risk assessment functions as the assistive tool for the communication between the industry and FDA as well as manufacturing and research and development departments within the company (Patricia, 2007). There are various regulatory authorities providing different validation guidelines for bioanalytical methods during the manufacturing process. It may lead to confusion for the manufacturer and thus is not suitable for process and product development. The risk of the confusion is assessed by the risk management method, hence this reduces the risk of the wrong decision being made during the process and helps to develop a high-quality product (Rozet et al., 2011). ICH Q9 guidelines describe the different methods of risk assessment. These methods may include fault tree analysis (FTA); failure mode effects analysis (FMEA); failure mode, effects and criticality analysis (FMECA); preliminary hazard analysis (PHA); hazard operability analysis (HAZOP); hazard analysis and critical control points (HACCP); quality function deployment; supporting statistical tools; risk ranking and filtering. Scientific knowledge about the risk and sufficient efforts for the solution of those risk factors are the main principles of the risk management of the process. Risk management is the collective duty of all the departments of the clinical, manufacturing, and sales unit (Ribeiro, 2013).

21.3.4 Design Space and Control Strategy The ICH Q8 defines the design space. Design space is the region where the material attributes and process parameters interact to assure quality. Hence, it explains the connection between CQAs and CPPs and determines the required operating ranges for product development. It is the region where a standard product can be produced (Bhatia et al., 2016). To ensure the consistency of the product quality, properties such as chemical, physical, and/or microbiological must be defined properly. The product would be achieving the required quality when all the operations are carried out within the design space. Thus, it describes a recognized choice of material attributes and/or process parameters that generate the product of desired quality. To achieve this, it is always advisable to choose a design space which could cover the entire process by providing improved flexibility in the design. Data from the previous studies of the product development stages will be very helpful when considering the construction of a design space in order to achieve the

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efficacy of the product by proper formulation based on the design and involvement of different parameters. Control strategy is the method which controls various parameters obtained from the current product development process to confirm the high efficacy of the process and produce high-quality product. The control strategy is defined by the QbD methodology where the CQAs and process capability parameters are taken into consideration. Generally, the control strategy includes all the parameters during the manufacturing process, such as raw material control, facility control, process control, in-process quality assurance, drug release testing, characterization method control, comparative study, and stability study (Gawade et al., 2013; Sk et al., 2013).

21.4 FACTORS AFFECTING DRUG PRODUCT PERFORMANCE Factors influencing the design and performance play a vital role in the drug product development and its performance. Therefore, they must be considered in manufacturing and clinical performance. These unique physicochemical factors show some applications in synthesis, and modifications which help principally to develop suitable candidates (Tekade et al., 2014). While developing the formulations, a predictable therapeutic response is required to be achieved by the developed candidate and should possess the ability to convert it into large-scale manufacture with reproducible product quality. To ensure product quality, various factors are to be considered to achieve the required quality and therapeutic response of the drug. These factors are discussed below:

21.4.1 Physicochemical Properties of Drug Substance The physical and chemical properties of active drug moiety are the pioneered concerned area in the product development. The scientists in the middle of the 20th century study their effects on the biological performance and clinical efficacy of the developed drug product (Barbour and Lipper, 2008). Many drug candidates are not able to maintain the pharmacokinetics and failure to do so will lead to rejection, as they would be unsuitable in terms of quality. The poor physicochemical properties of a potent drug during discovery and development would affect the costs of bringing it to a product stage by formulation. 21.4.1.1 Chemical Factors The different chemical options are available and used to enhance the stability and systemic availability of drugs. For example, esters produce the more stable derivatives of both acids and bases to prevent hydrolysis and become more stable. The stability, as well as solubility of both acids and bases, tends to rise when they are in the salt forms. Penicillin in the form of salt is more soluble, hence on administration, it shows higher blood concentration as compared to its acid form (Haveles, 2014). Thus, these will produce a proper response of the administered dose and will maintain the quality of the product by becoming stable or showing some other effects like solving solubility problems. The chemical degradation of the drug in the formulation may raise the impurity intensity and

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FIGURE 21.4 Crossing of different moieties across biological barrier.

FIGURE 21.5 Dynamic relationship in drug, drug product and pharmacologic effect.

thus decrease the potency of the drug whereas physical transformation would cause the product to be unsuccessful in the dissolution testing (one of the key CQAs). 21.4.1.2 Molecular Size and Diffusivity The diffusion of small drug molecules across the biological membrane is possible through the glycerol and water-filled free volume. The molecules which are larger than the membrane-pores do not cross the membrane and are retained on the sample side of the membrane. The small molecules and their buffer salts can cross biomembranes. Gases,

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hydrophobic molecules, and small polar uncharged molecules are candidates of interest which diffuse across phospholipid bilayers, but larger polar and charged molecules cannot cross the biomembranes (Maheshwari et al., 2012, 2015b). So, only small and relatively hydrophobic molecules can diffuse across a phospholipid bilayer at significant rates (Fig. 21.4). The ability of a drug to cross the membrane is considered as diffusivity. The molecular weight greater than 500 Da produces many difficulties to cross the membranes (Halligudi et al., 2012; Schalk and Mislin, 2017). 21.4.1.3 Aqueous Solubility and Dissolution Rate Solubility, a thermodynamic property of a compound, controls the fraction of drug being absorbed by passing the barriers of the gastrointestinal tract and reaching the systemic circulation (Fig. 21.5). The rate determining steps in the absorption of orally administered drugs are rate of dissolution (for lipophilic drugs, e.g., Griseofulvin) and rate of drug permeation through the biomembrane (for hydrophilic drugs, e.g., Neomycin). A preliminary requirement for the absorption of a drug is that it must be present in aqueous solution which depends on a drug’s aqueous solubility and dissolution rate. The drug having low aqueous solubility shows low dissolution rate hence it suffers from bioavailability (BA) problems (Savjani et al., 2012). The proper solubility and dissolution rate will enable the dosage form to deliver the proper amount of drug to maintain the proper therapeutic effects. 21.4.1.4 Amorphous and Crystalline Form The crystalline form has lower energy as compared to the amorphous form, hence it is more stable than the amorphous form. Hence, the crystalline form is explained in terms of the requirement of energy at the molecular level to break the stronger bonding. Solubility of compounds is dependent on the intermolecular hydrogen bonds between solute molecules and solvent molecules. Higher solubility correlates with higher dissolution rate and better BA of the compound. The amorphous form has higher dissolution rate than the crystal form as the crystal form has greater intermolecular forces (Yadav et al., 2009). An important factor for consistent therapeutic action is the drug product quality itself and the drug should be able to show a sufficient solubility profile which is better obtained in the amorphous form to maintain the quality. 21.4.1.5 Particle Size and Effective Surface Area Micronization produces smaller particles by size thus creating a greater effective surface area for the intimate contact between solid surface and aqueous solvent, thus causing higher dissolution rate. This finally leads to enhanced absorption efficiency. So, a reduction in particle size is used to boost the absorption of various poor water-soluble drugs, like digoxin, bishydroxycoumarin, nitrofurantoin, tolbutamide, and griseofulvin (Lancaster, 2013; Dizaj et al., 2015). Many of the newly developed and reported drug delivery carriers basically function via reduction of particle size down to the nanoscale (Tekade et al., 2017; Sharma et al., 2015; Maheshwari et al., 2015a). Maheshwari et al. formulated sustained release nifedipine tablets by making use of micronization technique. They prepared microsponge which was further granulated to form tablets of nifedipine (calcium channel blocker with poor water solubility) (Rahul et al., 2017).

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TABLE 21.3 Comparison of Stable and Metastable Form (Prasanthi et al., 2016) Stable Form

Metastable Form

• • • • •

• • • • •

Lowest energy state More stable form Highest melting point Least aqueous solubility Dissolution rate limited

Highest energy state Less stable form Lowest melting point Higher aqueous solubility Better absorption and bioavailability

21.4.1.6 Polymorphism and Amorphism When a substance occurs in more than one crystalline form it is designated as a polymorph, whereas amorphous form explains the quality of being amorphous or formless. In amorphous forms, no energy is considered to be necessary to break up the crystal lattice leading to faster dissolution of the drug moiety from drug product. So, the amorphous form is often selected over the crystalline form, and numerous drugs, including prednisolone and hydrocortisone, are marketed in the amorphic form (Censi and Di Martino 2015). The comparison between the stable and metastable form are given in Table 21.3. Polymorphic forms possess different chemical and physical properties such as chemical reactivity, melting point, apparent solubility, dissolution rate, vapor pressure, optical and mechanical properties, and density. These properties affect the process and manufacturing of drug product by affecting dissolution, bioavailability, and finally stability. So, polymorphism can influence the quality, safety, and efficacy of the formed drug product. 21.4.1.7 Partition Coefficient Partition coefficient (PC) gives the value of the drug partitioned between aqueous phase and nonaqueous phase. Ideally, for best possible absorption, a drug should have sufficient aqueous solubility to help it to dissolve in fluids at the absorption site and lipid solubility (Ko/w) good enough to facilitate the partitioning of the drug in the lipoidal biomembranes. So, as the PC (lipid solubility) increases, the percentage of drug absorbed also increases (Chillistone and Hardman, 2017). A special focus on the optimum region of lipophilicity and supervision of lipophilic efficiency indices will help significantly to improve overall quality of drugs at several stages of discovery. 21.4.1.8 pKa Ionization Constant pKa measures the strength of an acid or base determining the charge on the molecules at a given pH. Only undissociated and unionized molecules can cross the lipoidal membrane as compared to ionized molecules. Hence, the amount of the drug that exists in unionized form is a function of the dissociation constant of a drug and pH at the absorption site. Drugs existing in unionized form at the absorption site are good candidates for absorption while some drugs that exist in ionized form are poor candidates for absorption (Ashford, 2013). The performance of the acidic and basic drug molecules depends on the pKa and thus this is a very essential factor while considering the quality of the product.

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21.4.1.9 Solvates/Hydrates Solvates are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. The most common solvate is water. If water is incorporated as a solvent, then solvates are commonly known as hydrates. If water molecules are already present in a crystal structure as in hydrates form, the tendency of the crystal to attract additional water to initiate the dissolution process is reduced, and solvated (hydrated) crystals tend to dissolve more slowly than anhydrous forms, e.g., hydrous and anhydrous forms of caffeine, ampicillin, theophylline, mercaptopurine, and glutethimide. They are indirectly involving in affecting the clinical significance of the drug product (Savjani et al., 2012; Florence and Attwood, 2015). In case of solvates like theophylline monohydrate, water molecule acts as a bridge that links two molecules of theophylline which consequently requires breakage during the dissolution process. So, we can find that anhydrous theophylline is more soluble than its monohydrate form. However, in some cases, solvates may have elevated solubility as compared to the anhydrous form that reduces the affinity of the drug towards water which in turn reduces the solubility and dissolution. Thus, hydrates are less soluble than the amorphous forms. For example, the anhydrous form ampicillin is more soluble than the trihydrate form of ampicillin (Lee, 2014; Santos et al., 2014). As the formation of hydrates affects the solubility and stability of the product at different conditions, a careful and cautious choice of the specific form of cocrystals is essential to maintain the quality of a pharmaceutical product within particular standards.

21.4.2 Differences in Manufacturing Processes The competition and market pressures among the fast-growing industries for improved quality and better therapeutic effect have resulted in improved measurement and maintenance of product development record and different process involved throughout the product life cycle (Shahbaz et al., 2006). The manufacturing industries have collected and retained huge amounts of comprehensive data which could be related to designs, manufacture, operation and scheduling, processes achievement, and performance, as well as the use of specific machinery and other related resources, such as their sales, inventory control, and finally marketing. The basic idea of production or manufacturing is to generate (or produce) something that has a functional and useful structure. This structure (or form) is most probably predetermined and calculated using physical geometry and chemical nature (Duardo et al., 2015). The manufacturing progress or process improvement program should recognize all the critical development parameters, and they should be considered, monitored, or controlled to guarantee the product that is being produced has all the desired qualities. Significant variations between the manufacturing processes used to produce batches for pivotal clinical trials (safety, efficacy, BA, bioequivalence (BE)) or primary stability studies should be summarized to explain the effect of the differences on the manufacturability, performance, and quality achievement of the product. These data so obtained, should be represented in a way which facilitates comparison of the processes and the corresponding

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batch analyses information (Lawrence et al., 2014). The following information should be included: • • • • •

the identity of the product, e.g., batch number; utility of the produced batches, e.g., BE study batch number; the product development and manufacturing site; the product batch size; and any significant and relevant equipment differences, e.g., different design, operating principle, size.

The following manufacturing processes/phases are involved in the product development from start to finish of the product to maintain the quality of product (Kin et al., 2014). 21.4.2.1 Initial Planning Stage It is the first stages which depend on the specifications from the customer regarding the product plans and quality. These proposals estimate a rough cost which is calculated on the basis of the manufacturing method and overall schedule. Hence, it becomes necessary to consider the feasibility of manufacturing and its processes for the proposed product on a commercial scale. The initial planning stage of a product is helpful for proper designing that will help to ensure and meet the required cost, timeline, and quality targets. 21.4.2.2 Product Development Phase After establishing the feasibility of the project and its process, it becomes important to determine and explore the specifications of the drug product in more detail through working on the design and manufacture by selecting and obtaining the necessary processing data. This phase is helpful as it is important to maintain and achieve the specification planned in the earlier phase, i.e., initial planning stage. 21.4.2.3 Prototype Production/Evaluation The product plans and its quality specifications established from the customer through the use of product are used for the product manufacturing plans to determine the product development phase. It should follow the customer’s needs and specifications to establish the required quality standards. Its evaluation should be repeated during the process of product development, prototype production, and prototype until the prototype reaches the standard of quality required. Every batch’s products may have some defects, so manufacturers should concern the quality control department to reduce the defects to an acceptable point. Inspectors should have a regular inspection during this phase and quality product is allowed to be released for the next stage process. 21.4.2.4 Commercial Prototype Production Planning To build up a efficient manufacturing process line leading to the production of highquality products, a process should be adopted in such as a way that it supports the design of a core technique to fulfill the proposed pertinent manufacturing design and its layout. This phase is necessary and guarantees the commercial success of the high-quality

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product. It will help to cultivate, maintain, and increase a company’s market contribution by fulfilling a consumer requirement. 21.4.2.5 Commercial Prototype Production/Evaluation Depending on the manufacturing design and proposed layout in the commercial prototype production planning stage, the manufacturing line is built, and produces a commercial prototype. 21.4.2.6 Commercial Production Commercial production will start only on completion of all the necessary preparation. But modifications and improvements can be performed for the manufacturing line, making and encouraging the staff to improve their work continually. So, it is the effort of whole team which is actively cooperating to develop high-quality products as efficiently as possible. When the efforts of all the teammates are put together, then it will help to achieve the high-quality products by considering and strictly following the finalized protocol. 21.4.2.7 Inspection, Shipment, and Delivery The final developed products are closely evaluated and inspected both manually and by machine to ensure that there are no shortcoming, flaws, or defects. The goods that are approved by the inspection processes are ready to be used. For this, they are packed carefully to prevent contamination or damage and finally released into the market to be utilized by the customer. The inspection and quality control before shipment and delivery is necessary due to the following advantages: ensures accuracy, reduces the costs, protects the company name and its reputation, ensures the delivery of the right products, receives fewer complaints from customers, gathers data to improve efficiency, establishes a superior relationship with market, allows a justification to elevate their prices by maintaining and ensuring high-quality control, and helps to reduce marketing costs over time.

21.4.3 Differences in Excipients, Excipient Selection, and Quality Control Pharmaceutical inactive ingredients, commonly called excipients, are crucial to a drug product’s quality and its efficacy; hence they play a key function in formulation development. The pharmaceutical industries are focused on fulfilling a patient’s therapeutic needs by understanding the key features of active ingredients and inactive excipients in formulation progress, and they are evaluated for safety (Alsante et al., 2014). Excipients help in the manufacturing, administration, or absorption of dose to achieve the therapeutic response. Excipients, pharmacologically inert, can initiate, propagate, or take part in physical or chemical interactions with drug compounds, which may affect the success and quality of a medication. Excipients can show incompatibility and interactions with APIs. Hence, their selection and the understanding of drug excipients interactions is to be considered critically as they can influence the effectiveness and safety of the active moiety depending upon the administration route, e.g., excipients in solid dosage form can influence effectiveness and safety by enhancing or delaying gastrointestinal release.

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TABLE 21.4

Overview of Pharmaceutical Excipients

Category

Examples

Acidifying agent

Phosphoric acid, malic acid, fumaric acid, citric acid, succinic acid

Adsorbent

Colloidal silicon dioxide, cellulose, microcrystalline cellulose (MCC), silica gel

Alkalizing agent

Potassium bicarbonate, sodium citrate dehydrate, ammonium carbonate

Anionic surfactant

Sodium lauryl sulfate (SLS) and other alkyl sulfates and alkyl ethoxylate sulfates

Anticaking agent

Talc, calcium silicate, starch, magnesium carbonate, colloidal silicon dioxide, cellulose, calcium phosphate di or tri basic

Antifoaming agent

Dimethicone, insoluble oils, certain alcohols, stearates, glycols

Antimicrobial preservative

Benzyl alcohol, butyl paraben, glycerin, methyl paraben, propylene glycol, propylene paraben, potassium sorbate, sodium benzoate, sorbic acid, sodium propionate

Antioxidant

Butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), sodium metabisulfite

Antiseptic

Aluminum acetate, benzethonium chloride, hydrogen peroxide, iodophors, chlorhexidine gluconate, iodine, ethyl alcohol

Base for medicated confectionery

Sucrose, glucose

Binder

Alginate, candelilla wax, carnaubawax, cornstarch, lactose hydrous or anhydrous or monohydrate or spray dried, potato starch, sodium starch

Buffering agent

Calcium phosphate di or tri-basic, disodium hydrogen phosphate, sodium citrate dehydrate

Carbonating agent

Sodium carbonate, sodium bicarbonate, calcium carbonate, potassium carbonate

Cationic surfactant

Cetylpyridine chloride, cetrimide, benzalkonium chloride

Chelating agent/sequestering agent

Ethylene diamine tetra acetic acid (EDTA), monoisoamyl dimercaptosuccinic acid (MiADMSA), dimercaptosuccinic acid (DMSA)

Coating agent

Ethyl cellulose, gelatin, glyceryl behenate, hydroxypropyl cellulose, hydroxyl propyl methyl cellulose (HPMC), hypromellose, HPMC phthalate, methylcellulose, methacrylic acid copolymer, sodium carboxymethyl cellulose (Na-CMC), titanium dioxide

Coloring agent

Erythrosine sodium, iron oxides red or ferric oxide, iron oxide yellow

Detergent

SLS, tweens, spans

Diluent for dry-powder inhalers

Lactose hydrous or anhydrous or monohydrate or spray dried

Disinfectant

Benzyl alcohol, cetylpyridine chloride, propylene glycol

Disintegrant

Citric acid, MCC (Avicel), cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate (Continued)

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TABLE 21.4 (Continued) Category

Examples

Dispersing agent

Poloxamer 407 or 188 or plain, soap powder, turkey red oil, alkali sulfates, alkyl aryl sulfonates

Emollient

Dimethicone, glycerin, glyceryl monostearate, mineral oil

Emulsifying agent

Acacia, glyceryl monostearate, hydroxypropyl cellulose, methylcellulose, poloxamer 407 or 188 or plain, polyoxy140 stearate, SLS, stearic acid, sodium citrate dehydrate, colloidal silicon dioxide

Film-former

Copolyvidone, gelatin, HPMC, hypromellose

Flavoring fixative

Ethyl cellulose, gum arabic, monosodium glutamate (MSG)

Gelling agent

Gelatin, polyacrylamides, sodium alginate, magnesium aluminum silicate (veegum), poloxamers (pluronics), carbopols (carbomers), bentonite

Glidant

Colloidal silicon dioxide, cellulose, starch pregelatinized, starch, talc

Granulating agent

Copolyvidone, base for medicated confectionery

Humectants

Glycerin, propylene glycol, triacetin

Lubricant

Hydrogenated vegetable oil, mineral oil, polyethylene glycol (PEG), stearic acid, magnesium stearate, SLS

Lyophilization aid

Lactose hydrous or anhydrous or monohydrate or spray dried

Mucoadhesive

Polyethylene oxide, Acacia, chitosan, tragacanth

Nonionic surfactant

Glyceryl monooleate, tweens, spans

Nutrient and dietary supplementary

Calcium phosphate di or tribasic, minerals, fiber, fatty acids, or amino acids

Ointment base

PEG, white petrolatum, anhydrous lanolin, hydrophilic petrolatum

Oleaginous vehicle

Mineral oil, cocoa butter, white petrolatum

Opacifier

Titanium dioxide, ethylene glycol mono- and distearates, Cetyl alcohol, stearyl alcohol

Plasticizer

Glycerin, propylene glycol, triacetin, triethyl citrate, PEG

Rate-controlling polymer for sustained release

HPMC, hypromellose

Reducing agent

Cysteine HCl, copper hydride, ascorbic acid, alcohol dehydrogenase

Skin penetrant

SLS, dimethyl sulfoxide (DMSO)

Solubilizing agent

Cetylpyridine chloride, glyceryl monostearate, polysorbate 80, poloxamer 407 or 188 or plain, polyoxy140 stearate, stearic acid, sorbitan monooleate

Solvent

Benzyl alcohol, glycerin, mineral oil, PEG, propylene glycol, triacetin

Stabilizer for vitamins

Propylene glycol, disodium edetate, cysteine, thiourea, nicotinic acid

Stabilizing agent

Acacia, alginate, CMC, glyceryl monostearate, hydroxy propyl cellulose (HPC), HPMC, hypromellose, sodium alginate, Na-CMC (Continued)

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TABLE 21.4

757

(Continued)

Category

Examples

Suppository base

PEG, cocoa butter (Theobroma oil)

Suspending agent

Acacia, alginate, colloidal silicon dioxide, cellulose, CMC, gelatin, HPC, HPMC, hypromellose, MCC, methyl cellulose, polyvinylpyrrolidone (PVP), sucrose, sodium alginate, Na-CMC

Sustained-release ingredient

Glyceryl monostearate, carbopol, polyvinyl acetate (PVA), poly (ε-caprolactone) (PCL), poly (lactic-co-glycolic acid) (PLGA), poly (lactide acid) (PLA)

Sweetening agent

Confectioner sugar, glycerin, mannitol, sucrose, saccharin sodium

Tablet and capsule diluents

Calcium carbonate, confectioner sugar, cellulose, plain or anhydrous calcium phosphate, calcium hydrogen phosphate dehydrate, calcium phosphate di or tri basic, dibasic calcium phosphate, lactose hydrous or anhydrous or monohydrate or spray dried, MCC, mannitol, magnesium carbonate, magnesium oxide, sodium starch glycolate (SSG), starch pregelatinized, starch, sucrose, sodium chloride, talc

Tablet and capsule disintegrant

Croscarmellose sodium, CMC, MCC, methyl cellulose, PVP, SSG, starch pregelatinized, starch, sodium alginate, Na-CMC

Tablet and capsule lubricant

Calcium stearate, castor oil hydrogenated, glyceryl monostearate, glyceryl behenate, magnesium stearate, PEG, poloxamer 407 or 188 or plain, SLS, sodium benzoate, stearic acid, sodium stearyl fumarate, talc

Tablet binder

Acacia, alginic acid, copolyvidone, ethyl cellulose, gelatin, glyceryl behenate, HPC, HPMC, hypromellose, lactose hydrous or anhydrous or monohydrate or spray dried, methylcellulose, PVP, polyethylene oxide, starch pregelatinized (starch, potato, corn, wheat, rice), sodium alginate, Na-CMC

Tablet disintegrant

Alginic acid, colloidal silicon dioxide, crospovidone, sodium croscarmellose

Tablet filler

Sucrose, HPC, ethyl cellulose, sorbitol, starches, xylitol, lactose

Therapeutic agent

Calcium carbonate, sodium carbonate, magnesium hydroxide, aluminum hydroxide

Thickening agent

HPC, polyethylene oxide, Acacia, tragacanth, carbopol

Tonicity agent

Glycerin, glycine, mannitol, sodium chloride

Vehicle (bulking agent) for lyophilized preparations

Sucrose mannitol, dextran, sodium gluconate, lactose

Viscosity-increasing agent

Acacia, alginic acid, colloidal silicon dioxide, CMC, ethyl cellulose, gelatin, HPC, HPMC, hypromellose, methyl cellulose, sucrose, sodium alginate, Na-CMC

Water-absorbing agent

CMC, Na-CMC

Water-miscible cosolvent

Propylene glycol, alcohol, acetic acid, formic acid, pyridine, 1,4-dioxane

Wetting agents

Cetylpyridine chloride, poloxamer 407 or 188 or plain, polyoxy140 stearate, SLS

DOSAGE FORM DESIGN CONSIDERATIONS

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An excipient is the substance additionally used in the manufacturing process apart from the active drug(s) or prodrug present in a finished pharmaceutical dosage form and is purposely incorporated in a drug delivery system. Commercially, they are being used for increasing the bulkiness, lubrication, flowability, compressibility, and compatibility that can provide the specific and desired properties to the finishing product, such as modifying drug release, controlling the drug release process in the case where quick assimilation could lead to gastric exasperation or stomach distress. They are categorized as binders, disintegrants, diluents, glidants, lubricants, emulsifying solubilizing agents, coating agents, sweetening agents, antimicrobial preservatives, etc. (Table 21.4). They have been categorized into two categories (1) compendial excipients (2) noncompendial excipients. The composition consistency of compendial excipients are detailed in monographs such as the United States Pharmacopeia (USP), National Formulary (NF), Indian Pharmacopoeia (IP), British Pharmacopoeia (BP), etc. Hence, they are the better-characterized excipients and possess the required qualities. They are preferred over the noncompendial excipients for pharmaceutical formulations, although noncompendial excipients can also be used in pharmaceutical formulations (Chang et al., 2013). These excipients should be selected so as to provide compatible and toxicity-free excipients which can be linked to various unit processes in product development. The functional and performance characteristics of an excipient significantly depend on its quality in the development and manufacturing. The performance of any dosage form is based on the physical and chemical properties of the excipient used. To achieve the required specification, it becomes necessary to select the specific tests and specifications to ensure the performance of excipient, which can be achieved by a complete understanding of the physical and chemical properties of each excipient in the final drug product (Lawrence et al., 2014). Hence, both pharmaceutical users and excipient suppliers should identify and control excipient critical material attributes for the proposed drug application use. Factors such as the concentration, the type, and characteristics of excipients that can affect the performance of the drug product (such as stability, BA, etc.) or manufacturing should be consulted relative to the respective role of each excipient. The trace levels of impurities in some cases in the excipient could have high impact on product performance. For example, for a drug which is prone to oxidation, their oxidative product should be considered as they may significantly affect drug product stability and, subsequently, its purity/impurity profile could be affected (Kristensen, 2007; Wu et al., 2011). With the escalating globalization of the pharmaceutical industry, numerous challenges arise with the sourcing of excipients available from multiple manufacturers and suppliers. This could lead to variation in batch-to-batch, lot-to-lot, or supplier-to-supplier material that could create issues with performance in equivalence and efficacy. Manufacturing a quality pharmaceutical product requires well-defined excipients and processes that yield consistent results (Thacker et al., 2010; Van Buskirk et al., 2014). Some of the excipients are used to enhance the product taste and improve appearance along with the improvement in the patient compliance, especially in the case of children. Although technically “inactive” from a therapeutic point, they are critical and fundamental components which are providing the gear to the modern drug product development (Daniels et al., 2016).

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21.5 DRUG PRODUCT QUALITY AND DRUG PRODUCT PERFORMANCE

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21.5 DRUG PRODUCT QUALITY AND DRUG PRODUCT PERFORMANCE Drug product quality includes the different analytical procedures and tests which will give the values in the acceptance criteria. These tests are responsible for confirmation of the quality of drug products, substances, any intermediate(s), raw material involved, containers, and any other material or components of the production process. Hence, they act as regular and predictable methods to measure the safety of the product development, thus helping the organization to surmount any science and technology issues. Product performance and attributes are significant factors that affect product quality (Thoorens et al., 2014). Quality must be maintained throughout the different development stages starting from the initial, i.e., research, until the final development. This is achieved by practicing procedures and systems that are followed during the development and manufacture of the drug product. These procedures and methods adopted for the purpose must be able to evaluate the effect of the physical and chemical properties of the drug, drug stability, and its production at a large-scale for the aforesaid biologic performance of the drug (Du et al., 2011). Drug product performance means how and in what quantity the drug is reaching systemic circulation is dependent upon the drug release from the drug product. Hence, its performance depends upon the BA which is related to pharmacodynamic effects whether favorable or unfavorable. Hence, drug product quality is of great concern for the clinical efficacy which is responsible for the drug product performance. BA, the amount of active drug available in the systemic circulation, is an important feature of drug product quality and is affected by the different factors (Savjani et al., 2012; Kollipara and Gandhi, 2014). It provides the information of in vivo performance of a new drug product. This will help to setup the safety of the product and can be used in clinical safety and efficacy studies. Another study for the drug product performance includes the BE studies which compare the BA of the drug in one product with the other drug products. Thus, for the in vivo performance, BA and BE are considered to be very important (Zaman et al., 2016). Quality assurance and quality control (QA/QC) are responsible for all aspects related to product QA/QC and the completion of necessary documentation to verify the work performed and its authenticity. The results so produced will be able to judge whether to approve or reject the different parameters used in the product development, such as chemicals, process or process variables, packaging material, and labeling. Hence, it is involved in ensuring that all test reports are verified to meet the contract requirements, and all the documentation has been compiled in a final presentable manner, in harmony with the conditions of the contract. QA/QC department is accountable for approving or disapproving drug product, processing, and packaging for the product which are held under contract by the company. The pharmacodynamic, pharmacokinetic, and in-vitro in-vivo correlation (IVIVC) models are used to study the effect of manufacturing differences and variability on clinical performance/efficacy of a developed dosage system (Munoz, 2013; Kaur et al., 2015).

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760

21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY

21.6 SCALE-UP AND POSTAPPROVAL CHANGES SUPAC is the method of developing the new product and scaling up the batch size of the developed and manufactured goods. It includes the changes and scale-up in the composition, manufacturing process, batch size, manufacturing apparatus and equipment, and change of manufacturing location. The FDA has published various guidelines for SUPAC. They are designated as (1) Supac-IR (for immediate drug release solid oral dosage form; (2) Supac-MR (for modified drug release solid oral dosage form); and (3) SUPAC-SS (for nonsterile semisolid dosage form including lotions, creams, ointments, and gel) (FDA, 2014). These guidelines provide recommendations for postapproval changes in component or composition, location of manufacturing, scale-up of manufacture, and the manufacturing variables. It includes the process and equipment (from nonautomated to automated or vice versa moving of ingredients, or use of some alternative and optional equipment of same design and operating on same principle with similar or dissimilar capacity) (FDA, 1997). While following the FDA guidelines, the focus must be on modification in the number of excipients in the formulation without changing the amount of the drug material (Van Buskirk et al., 2014). The FDA is playing a greater effort to check their feasibility and approaches to be concurrent with the modern manufacturing practices.

21.6.1 FDA Level of Changes The FDA has recommended several steps that will lessen the regulatory burden related to the retaining of approved status of existing drug products when they undergo changes in their content and/or their manufacture. The FDA does this by making the companies and organization follow the SUPAC guidelines (Khetani and Bhatia, 2008; Anand et al., 2011). For that they have used the certain levels which are as follows: Level 1: Includes the changes which can have any detectable effect on formulation quality, value, and performance. It includes the examples such as changes in the flavors, color, excipients which are expressed as the percentage (w/w) of entire formulation. The changes should also be reported in the final annual statement and report. It includes the requirements related to the documentation application and/or compendial release requirements, announcement of changes and submission of updated batch records in annual report, report of one batch kept for long-term stability in yearly report, no dissolution or in vivo testing, and filing documentation with yearly report (long-term stability commitment). Level 2: Includes the changes which could have considerable effects on the formulation quality and performance. It includes changes in the different technical grade of excipient (such as Avicel PH-102 and Avicel PH-200), changes expressed in terms of percent (w/w of total formulation). The requirements of level 2 includes stability testing, such as one batch with 3 months accelerated stability data and one batch on long-term stability and dissolution documentation maintenance, such as case B testing, filing documentation with earlier approved supplement and its annual report. Level 3: Includes the changes which have significant effects on formulation quality, value, and performance. It includes qualitative or quantitative chemical excipient

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21.6 SCALE-UP AND POSTAPPROVAL CHANGES

761

changes to a narrow therapeutic drug beyond the range for level 1. All other drugs which are not meeting the dissolution criteria are considered as level 2. Changes in the process or formulation may require costly clinical and bioclinical studies to establish safety and efficacy and an earlier approval declaration from the FDA, which provides the information that the changes made by you have been accepted. This process can take about 6 or more months; hence it may lead to delay in process validation of stability studies and delay in time for the commercial launch of the product.

21.6.2 Assessment of the Effects of the Changes One of the major challenges to the pharmaceutical industries is constantly varying requirements and changes in the initial stage of product development cycle due to the unavailability of proper and adequate information. Numerous tools, process, and methods address how changes affect additional and essential product components (Stark, 2015). Thus, they may result in changes of the development cost and time. Hence, additional effort should be performed, and estimation of its impact on development must be correlated. ICH Guideline Q5 provides principles to compare and correlate biological/biotechnological products before and after changes performed in the development and manufacturing process for the drug product or drug substance (Guideline, 2013).

21.6.3 Critical Manufacturing Variables Critical manufacturing variables are the key variables in the pharmaceutical manufacturing affecting the production progression and related to the quality of the product development. These are the attributes to be monitored to spot deflections in standardized and uniform production operations and product output worth or variations in CQAs. These

FIGURE 21.6 Linking Patient to Product to Process.

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21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY

variables affect a quality of the product. Hence, they should be controlled or monitored to guarantee the process to produce the desired quality. For example, in pharmaceutical tablet manufacturing processes, the most important and major source of trouble is the (lot-to-lot) variability and inconsistency of the incoming raw materials which affect the drug product quality (Mitchell, 2014). To overcome and minimize the undesired effect, novel modeling, and process optimization policies are designed and opted to compensate raw material variability and their proper utilization. The effectiveness of the methodologies could be successfully achieved by obtaining interrelationships among the three sources of variability, i.e., attributes, parameters, materials, as defined by the ICH-Q8 guideline. CPPs are the process parameters whose variability has an impact on a CQAs and therefore should be monitored or controlled to ensure the process produces the desired quality (FDA, 2006; Short et al., 2011) (Fig. 21.6). The different process variables which could affect the product quality and its efficacy for the proper disease management include particle size distribution, loading level, blending, type and geometry of mixer, number of revolutions including time and speed, order of addition, holding time, etc.

21.6.4 Bulk Active Postapproval Changes The FDA has issued a Guideline for Industry entitled “BACPAC I: Intermediates in Drug Substance Synthesis” in 2001 that offers clarification as well as regulatory relief for late-stage active pharmaceutical ingredient (API) postapproval changes. Bulk active postapproval changes (BACPAC) I covers all processes and the different steps involved along with the intermediates. BACPAC helps in successful reviewing of the postapproval arena of SUPAC which helps in covering the documents for the complete scope of API used in the processes (Nusim, 2016). Supporting and assisting data should be incorporated in the regulatory submissions. Manufacturing changes of the API may result in the change in its quality attributes. These quality attributes include solid-state properties, chemical purity, and residual solvents. They provide the guidance for the development of bulk active product manufacturing and its synthesis along with the API and their benefits for the design and development of new drug product (Van Buskirk et al., 2014). The difference in the solid-state properties of the API may alter and affect the manufacture of the dosage form or/and product performance. One of such factors includes change in particle size resulting in the difference and altering the API bulk density or/and tablet hardness, whereas API solubility and stability may be affected by different polymorphs of the API used. Changes in particle size and polymorph may affect the drug’s BA in vivo. Moreover, the pharmacologic properties of the excipient(s) and vehicle used may influence product quality and performance rate (Nusim, 2016). After the issues of BACPAC I, FDA has released the BACPAC II for controlling and observation of the post changes. FDA also warned that BACPAC II would not achieve regulatory relief. So BACPAC II was subsequently withdrawn and in 2006 BACPAC I

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21.7 POSTMARKETING SURVEILLANCE

763

guidance was withdrawn officially. So, at present no postapproval guidance for APIs has been issued (Nusim, 2016).

21.7 POSTMARKETING SURVEILLANCE The consumption of the drugs in the today’s world is increasing at higher rates as compared to the 1950s and 1960s. According to the FDA, a new and novel drug should be “safe and efficacious for its intended use” when it is to be released in the market, providing positive benefit to harm balance, and showing its beneficial and positive effects. The randomized clinical trials by the regulatory authorities before drug approvals provide the information regarding the favorable effects which can overcome any potential (Furberg, 2011). It becomes necessary to monitor the approved drugs by collecting information regarding medication problems to maintain the quality of marketed pharmaceutical products. This monitoring of marketed product after the approval by the FDA is called postmarketing surveillance (PMS). It is an important part of product development that is necessary to observe the safety and assurance of a pharmaceutical drug or medical device (Waning et al., 2001). This will help in perceiving the negative or positive effects over an extended period and provide the evaluation and monitoring information of the ADRs. PMS requires special attention in case of pediatric pharmacovigilance as the disorders and diseases of childhood vary quantitatively and qualitatively. It starts immediately after the marketing of the product. In these cases, the safety of medicine and its monitoring is of paramount importance when the drug is under the clinical development. Different cases have been reported where the different medicines were withdrawn from the market because of ADRs and these are considered as postmarketing withdrawal (Onakpoya et al., 2016a, 2016b). Thus, it becomes significant to be very attentive for ADRs-related spontaneous problems and the ways to crack them. The attentive measures taken by the authorities thus have shortened the period between launch date and reports of ADRs in the past few decades. Different approaches used by PMS to monitor the safety of licensed drugs are (1) spontaneous reporting, (2) databases, (3) prescription even monitoring, (4) electronic health records, (5) patient registries, and (6) record linkage between health databases. The evidences such as observational studies, systematic reviews, anecdotal reports, animal data, or clinical trials provide the ADRs knowledge and thus speed up the postapproval withdrawal of medicinal products from the market. Thus, this removal of formerly approved products from the market can lead to the loss of trust in medicinal product by the public which ultimately leads to the loss of profit for drug manufacturers. Challenge - dechallenge- rechallenge (CDR) is a method which is providing the protocol for testing the medicinal products and kits for their ADRs at each stage. Challenge is the drug administration to the patient for the period of the treatment. The response observed for the reduction or removal of ADRs on withdrawal or removal of a drug from a patient is commonly known as dechallenge and is crucial for proper prescription.

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21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY

Dechallenge is the stopping of the drug, generally after an adverse incident or as the last part of a designed treatment. It may be a positive dechallenge (adverse event disappearing after the stopping of the drug) or a negative dechallenge (adverse event not disappearing after the stopping of the drug). Rechallenge is the restarting of the same drug after being stopped; generally for an adverse event it is necessary to authenticate the cause and link of ADRs. It may be a positive rechallenge (adverse event repeating after restarting the drug) or a negative rechallenge (the adverse event does not repeat after the drug is restarted) (Meyboom, 2013; Banu et al., 2014). There are many drugs which have been banned by the FDA in many countries due to their serious toxic effects. Nimesulide is a common example which has been banned in many countries like Japan, Spain, India, Israel, Finland, Turkey, and Sri Lanka as it is responsible for increased chances of hepatotoxicity. Hence, Nimesulide has not yet been approved by FDA (Ahmad et al., 2014).

21.8 CONCLUSION The quality of the production process influences the development of a drug product. The maintenance of the quality and safety of a product during the production process and postproduction process is the key consideration and will assist industry for a booming product development and to expedite regulatory approval. This chapter provides the information and understanding of the correlation between the drug product development and its efficacy for the formulated dosage form of active moiety. The topics discussed in this chapter help the formulators to move with the required demand of the market regarding its market value and availability in the product. The clinical efficacies should be achieved by applying the biopharmaceutics information for the design of the new product and are important to be considered during the product development process. It should be kept in consideration that for the high-quality product therapeutics, the objectives are to achieve maximum BA and to minimize adverse effects.

Acknowledgment The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant allocated to Dr. Tekade for research work on gene delivery and N-PDF funding (PDF/2016/003329) for work on targeted cancer therapy. RT would also like to thank NIPER-Ahmedabad for providing research support for research on cancer and diabetes. The authors also acknowledge the support by Fundamental Research Grant (FRGS) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery. Disclosures: There are no conflicts of interest and disclosures associated with the manuscript.

ABBREVIATIONS ADRs API BA

Adverse drug reactions Active pharmaceutical ingredient Bioavailability

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REFERENCES

BACPAC BE BHA BHT CDR cGMPs CpK CPPs CQAs DMSA DMSO EDTA FDA FMEA FMECA FTA HACCP HAZOP HPC HPMC ICH IVIVC MCC MiADMSA MSG Na-CMC PC PCL PEG PHA PLA PLGA PMS PVA PVP QA/QC QbD QTPP SLS SSG SUPAC

765

Bulk active postapproval changes Bioequivalence Butylated hydroxy anisole Butylated hydroxy toluene Challenge - dechallenge - rechallenge Current good manufacturing practices Process capability index Critical process parameters Critical quality attributes Dimercaptosuccinic acid Dimethyl sulfoxide Ethylene diamine tetraacetic acid US Food and Drug Administration Failure mode effects analysis Failure mode, effects, and criticality analysis Fault tree analysis Hazard analysis and critical control points Hazard operability analysis Hydroxypropyl cellulose Hydroxyl propyl methyl cellulose International Conference on Harmonization In-vitro in-vivo correlation Microcrystalline cellulose Monoisoamyl dimercaptosuccinic acid Monosodium glutamate Sodium carboxy methyl cellulose Partition coefficient Poly ε-caprolactone Polyethylene glycol Preliminary hazard analysis Poly (lactide acid) Polylactic-co-glycolic acid Postmarketing surveillance Polyvinyl acetate Polyvinylpyrrolidone Quality assurance and quality control Quality by design Quality target product profile Sodium lauryl sulfate Sodium starch glycolate Scale-up and postapproval changes

References Abdul-Ghani, M., Migahid, O., Megahed, A., Adams, J., Triplitt, C., DeFronzo, R.A., et al., 2017. Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: the Qatar Study. Diabetes Care 40 (3), 325 331. Achan, J., Talisuna, A.O., Erhart, A., Yeka, A., Tibenderana, J.K., Baliraine, F.N., et al., 2011. Quinine, an old antimalarial drug in a modern world: role in the treatment of malaria. Malar. J. 10 (1), 144. Ahmad, A., Patel, I., Sanyal, S., Balkrishnan, R., Mohanta, G.P., 2014. A study on drug safety monitoring program in India. Ind. J. Pharm. Sci. 76 (5), 379. Alomar, M.J., 2014. Factors affecting the development of adverse drug reactions. Saudi Pharm. J. 22 (2), 83 94.

DOSAGE FORM DESIGN CONSIDERATIONS

766

21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY

Alsante, K.M., Huynh-Ba, K.C., Baertschi, S.W., Reed, R.A., Landis, M.S., Furness, S., et al., 2014. Recent trends in product development and regulatory issues on impurities in active pharmaceutical ingredient (API) and drug products. Part 2: safety considerations of impurities in pharmaceutical products and surveying the impurity landscape. AAPS PharmSciTech 15, 237 251. Anand, O., Lawrence, X.Y., Conner, D.P., Davit, B.M., 2011. Dissolution testing for generic drugs: an FDA perspective. AAPS J. 13 (3), 328. Angelakis, E., Million, M., Kankoe, S., Lagier, J.C., Armougom, F., Giorgi, R., et al., 2014. Abnormal weight gain and gut microbiota modifications are side effects of long-term doxycycline and hydroxychloroquine treatment. Antimicrob. Agents Chemother. 58 (6), 3342 3347. Arcangelo, V.P., Peterson, A.M. (Eds.), 2006. Pharmacotherapeutics for Advanced Practice: A Practical Approach, vol. 536. Lippincott Williams & Wilkins, Philadelphia, United States. Aronson, J.K., 2009. Medication errors: definitions and classification. Br. J. Clin. Pharmacol. 67 (6), 599 604. Ashford, M., 2013. Bioavailability—physicochemical. Aulton’s Pharmaceutics E-Book: The Design and Manufacture of Medicines. Elsevier Health Sciences, United States, p. 314. Banu, A.B., Balamurugan, S.A.A., Thirumalaikolundusubramanian, P., 2014. Detection of dechallenge in spontaneous reporting systems: a comparison of Bayes methods. Ind. J. Pharmacol. 46 (3), 277. Barbour, N.P., Lipper, R.A., 2008. Introduction to biopharmaceutics and its role in drug development. Biopharmaceutics Applications in Drug Development. Springer, Boston, MA, pp. 1 25. Bhatia, H., Read, E., Agarabi, C., Brorson, K., Lute, S., Yoon, S., 2016. A design space exploration for control of Critical Quality Attributes of mAb. Int. J. Pharm. 512 (1), 242 252. CDC, Part 2: General Approach to Treatment and Treatment of Uncomplicated Malaria. ,https://www.cdc.gov/ malaria/diagnosis_treatment/clinicians2.html. (accessed 08.09.17). Caldemeyer, L., Dugan, M., Edwards, J., Akard, L., 2016. Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia. Curr. Hematol. Malign. Rep. 11 (2), 71 79. Censi, R., Di Martino, P., 2015. Polymorph impact on the bioavailability and stability of poorly soluble drugs. Molecules 20 (10), 18759 18776. Chang, R.K., Raw, A., Lionberger, R., Yu, L., 2013. Generic development of topical dermatologic products: formulation development, process development, and testing of topical dermatologic products. AAPS J. 15 (1), 41 52. Chester Wasko, M., Dasgupta, A., Ilse Sears, G., Fries, J.F., Ward, M.M., 2016. Prednisone use and risk of mortality in patients with rheumatoid arthritis: moderation by use of disease-modifying antirheumatic drugs. Arthritis Care Res. 68 (5), 706 710. Chillistone, S., Hardman, J.G., 2017. Factors affecting drug absorption and distribution. Anaesth. Intens. Care Med. 18 (7), 335 339. Costedoat-Chalumeau, N., Dunogue´, B., Leroux, G., Morel, N., Jallouli, M., Le Guern, V., et al., 2015. A critical review of the effects of hydroxychloroquine and chloroquine on the eye. Clin. Rev. Allergy Immunol. 49 (3), 317 326. Daniels, R., Hoffmann, A., Go¨tz, M.R., Fischer, J.T., Holmgren, K., Symrise, A.G., 2016. Oral Dosage Form. U.S. Patent Application15/261,042. Deihimi, M., Moghbelinejad, S., Najafipour, R., Parivar, K., Nassiri-Asl, M., 2017. The effects of rutin on the gene expression of Dazl, Bcl2, and Caspase3 in idarubicin-induced testicular damages in mice. Iran. Red Crescent Med. J. 19, 4. Dizaj, S.M., Vazifehasl, Z., Salatin, S., Adibkia, K., Javadzadeh, Y., 2015. Nanosizing of drugs: effect on dissolution rate. Res. Pharm. Sci. 10 (2), 95. Du, B., Daniels, V.R., Vaksman, Z., Boyd, J.L., Crady, C., Putcha, L., 2011. Evaluation of physical and chemical changes in pharmaceuticals flown on space missions. AAPS J. 13 (2), 299 308. Duardo, K.G., Curbelo, Y.P., Pous, J.R., Lego´n, E.Y.R., Ramı´rez, B.S., de la Luz Herna´ndez, K.R., et al., 2015. Assessment of the impact of manufacturing changes on the physicochemical properties and biological activity of Her1-ECD vaccine during product development. Vaccine 33 (35), 4292 4299. Ebbers, H.C., de Tienda, N.F., Hoefnagel, M.C., Nibbeling, R., Mantel-Teeuwisse, A.K., 2016. Characteristics of product recalls of biopharmaceuticals and small-molecule drugs in the USA. Drug Discov. Today 21 (4), 536 539. Edwards, I.R., Bencheikh, R.S., 2016. Pharmacovigilance is. . . vigilance. Drug Safety 39 (4), 281 285. Eichler, H.G., Abadie, E., Breckenridge, A., Flamion, B., Gustafsson, L.L., Leufkens, H., et al., 2011. Bridging the efficacy-effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat. Rev. Drug Discov. 10 (7), 495.

DOSAGE FORM DESIGN CONSIDERATIONS

REFERENCES

767

Evans, N., Swan, J., 2015. Prevention of Medical Errors for Florida Occupational Therapists. FDA, September 1997. Guidance for industry SUPAC-MR: Modified release solid oral dosage forms scale-up and postapproval changes: chemistry, manufacturing, and controls. In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation. FDA, 2004. Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach. FDA, 2006. Guidance for Industry: Q9 Quality Risk Management. FDA, 2009a. Guidance for Industry: Q8 (2) Pharmaceutical Development. FDA, 2009b. Guidance for Industry: Q10 Pharmaceutical Quality System. FDA, 2013. Strategic Plan for Preventing and Mitigating Drug Shortages. FDA, 2014. Guidance for Industry on Scale-Up Post-Approval Changes: Manufacturing Equipment Addendum; Availability. ,http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.. FDA, 2017. Safety. ,https://www.fda.gov/Safety/Recalls/ucm165546.htm. (accessed 20.07.17). Fahrenkopf, A.M., Sectish, T.C., Barger, L.K., Sharek, P.J., Lewin, D., Chiang, V.W., et al., 2008. Rates of medication errors among depressed and burnt out residents: prospective cohort study. BMJ 336 (7642), 488 491. Falzon, D., Schu¨nemann, H.J., Harausz, E., Gonza´lez-Angulo, L., Lienhardt, C., Jaramillo, E., et al., 2017. World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update. Eur. Respir. J. 49 (3), 1602308. Ferner, R.E., Aronson, J.K., 2006. Clarification of terminology in medication errors. Drug Safety 29 (11), 1011 1022. Filik, R., Purdy, K., Gale, A., Gerrett, D., 2006. Labeling of medicines and patient safety: evaluating methods of reducing drug name confusion. Human Factors 48 (1), 39 47. Florence, A.T., Attwood, D., 2015. Physicochemical Principles of Pharmacy: In Manufacture, Formulation and Clinical Use. Pharmaceutical Press, London, p. 21. Focaccetti, C., Bruno, A., Magnani, E., Bartolini, D., Principi, E., Dallaglio, K., et al., 2015. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One 10 (2), e0115686. Furberg, C.D., 2011. Understanding drug safety and how to maximize it for patients. J. Am. Acad. Phys. Assist. 24 (11), 16 17. Gawade, A., Chemate, S., Kuchekar, A., 2013. Pharmaceutical Quality by Design: A new approach in product development. Res. Rev.: J. Pharm. Pharm. Sci. 2 (3), 1 8. Glodek, M., Liebowitz, S., McCarthy, R., McNally, G., Oksanen, C., Schultz, T., et al., 2006. Process robustness—a PQRI white paper. Pharm. Eng. 26 (6), 1 11. Goodman, C.A., Coleman, P.G., Mills, A.J., 2001. Changing the first line drug for malaria treatment—cost-effectiveness analysis with highly uncertain inter-temporal trade-offs. Health Econ. 10 (8), 731 749. Grissinger, M., 2012. Safeguards for using and designing automated dispensing cabinets. Pharm. Ther. 37 (9), 490. Guideline, I.H.T., 2013. Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process Q5E. Halligudi, N., Mullaicharam, A.R., Al-bahri, H., 2012. Molecular modifications of ibuprofen using Insilico modeling system. Int. J. Nutr. Pharmacol. Neurol. Dis. 2 (2), 156. Haveles, E.B., 2014. Applied Pharmacology for the Dental Hygienist-E-Book. Elsevier Health Sciences, Missouri, United States. Ho, W.E., Peh, H.Y., Chan, T.K., Wong, W.F., 2014. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol. Ther. 142 (1), 126 139. HPRA, Quality defects and recalls. ,https://www.hpra.ie/homepage/medicines/regulatory-information/market-compliance-and-surveillance/quality-defects-and-recalls. (accessed 15.07.17). HSA, Guidance for Industry Reporting of Therapeutic Product Defects and Recall of Therapeutic Products. ,http://www.hsa.gov.sg/content/dam/HSA/HPRG/Safety_Alerts_Product_Recalls_Enforcement/Guidance %20for%20Industry_Reporting%20of%20therapeutic%20product%20defects%20and%20recall%20of%20therapeutic%20products_Nov2016_v1.pdf. (accessed 06.09.17). Ishtiaq, S., Edwards, S., Sankaralingam, A., Evans, B.A.J., Elford, C., Frost, M.L., et al., 2015. The effect of nitrogen containing bisphosphonates, zoledronate and alendronate, on the production of pro-angiogenic factors by osteoblastic cells. Cytokine 71 (2), 154 160. Jnawali, H.N., Ryoo, S., 2013. First and second line drugs and drug resistance. Tuberculosis-Current Issues in Diagnosis and Management. InTech.

DOSAGE FORM DESIGN CONSIDERATIONS

768

21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY

Karagiannis, T., Paschos, P., Paletas, K., Matthews, D.R., Tsapas, A., 2012. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 344, e1369. Kaur, P., Jiang, X., Duan, J., Stier, E., 2015. Applications of in vitro in vivo correlations in generic drug development: case studies. AAPS J. 17 (4), 1035 1039. Keers, R.N., Williams, S.D., Cooke, J., Ashcroft, D.M., 2013. Causes of medication administration errors in hospitals: a systematic review of quantitative and qualitative evidence. Drug Safety 36 (11), 1045 1067. Kelley, B., Cromwell, M., Jerkins, J., 2016. Integration of QbD risk assessment tools and overall risk management. Biologicals 44 (5), 341 351. Khetani, S.R., Bhatia, S.N., 2008. Microscale culture of human liver cells for drug development. Nat. Biotechnol. 26 (1), 120. Kim, K.K., 2011. Nicolau syndrome in patient following diclofenac administration: a case report. Ann. Dermatol. 23 (4), 501 503. Kin, S.T.M., Ong, S.K., Nee, A.Y.C., 2014. Remanufacturing process planning. Proc. CIRP 15, 189 194. Kollipara, S., Gandhi, R.K., 2014. Pharmacokinetic aspects and in vitro in vivo correlation potential for lipidbased formulations. Acta Pharm. Sin. B 4 (5), 333 349. Kristensen, H.G., 2007. Functionality-related characteristics of excipients. Pharm. Technol. 31 (10), 134. Kuhn, M., Letunic, I., Jensen, L.J., Bork, P., 2015. The SIDER database of drugs and side effects. Nucleic Acids Res. 44 (D1), D1075 D1079. Kuyucu, S., Mori, F., Atanaskovic-Markovic, M., Caubet, J.C., Terreehorst, I., Gomes, E., et al., 2014. Hypersensitivity reactions to non-betalactam antibiotics in children: an extensive review. Pediatr. Allergy Immunol. 25 (6), 534 543. Kweder, S.L., Dill, S., 2013. Drug shortages: the cycle of quantity and quality. Clin. Pharmacol. Ther. 93 (3), 245 251. Lai, H., Singh, N.P., Sasaki, T., 2014. Artemisinin. Encyclopedia of Cancer. Elsevier, pp. 1 4. Lancaster, R., 2013. Pharmacology in Clinical Practice. Elsevier. Langer, S.W., 2014. Dexrazoxane for the treatment of chemotherapy-related side effects. Cancer Manage. Res. 6, 357. Lawrence, X.Y., Kopcha, M., 2017. The future of pharmaceutical quality and the path to get there. Int. J. Pharm. 528, 354 359. Lawrence, X.Y., Amidon, G., Khan, M.A., Hoag, S.W., Polli, J., Raju, G.K., et al., 2014. Understanding pharmaceutical quality by design. AAPS J. 16 (4), 771 783. Lee, E.H., 2014. A practical guide to pharmaceutical polymorph screening & selection. Asian J. Pharm. Sci. 9 (4), 163 175. Li, J., Qiao, Y., Wu, Z., 2017. Nanosystem trends in drug delivery using quality-by-design concept. J. Controlled Release 256, 9 18. Lipsitz, Y.Y., Timmins, N.E., Zandstra, P.W., 2016. Quality cell therapy manufacturing by design. Nat. Biotechnol. 34 (4), 393 401. Macy, E., 2014. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr. Allergy Asthma Rep. 14 (11), 476. Maheshwari, R.G., Tekade, R.K., Sharma, P.A., Darwhekar, G., Tyagi, A., Patel, R.P., et al., 2012. Ethosomes and ultradeformable liposomes for transdermal delivery of clotrimazole: a comparative assessment. Saudi Pharm. J. 20 (2), 161 170. Maheshwari, R., Tekade, M., Sharma, P.A., Tekade, R.K., 2015a. Nanocarriers assisted siRNA gene therapy for the management of cardiovascular disorders. Curr. Pharm. Des. 21 (30), 4427 4440. Maheshwari, R.G., Thakur, S., Singhal, S., Patel, R.P., Tekade, M., Tekade, R.K., 2015b. Chitosan encrusted nonionic surfactant based vesicular formulation for topical administration of ofloxacin. Sci. Adv. Mater. 7 (6), 1163 1176. Martins, A.C., Cayotopa, A.D.E., Klein, W.W., Schlosser, A.R., Silva, A.F.D., Souza, M.N.D., et al., 2015. Side effects of chloroquine and primaquine and symptom reduction in malaria endemic area (Maˆncio Lima, Acre, Brazil). Interdiscip. Perspect. Infect. Dis. 2015, 7. Meyboom, R., 2013. Intentional rechallenge and the clinical management of drug-related problems. Drug Safety 36 (3), 163 165.

DOSAGE FORM DESIGN CONSIDERATIONS

REFERENCES

769

Mitchell, M., 2014. Determining criticality-process parameters and quality attributes Part II; Design of experiments and data-driver criticality. BioPharam Jan, 1, 9. Mohammadi, A.B., Noshad, H., Ostadi, A., Ghaffari, A.R., Dinevari, M., 2015. Medication error, what is the reason? Iran. J. Toxicol. 9 (30), 1408 1410. Munoz, A.M. (Ed.), 2013. Sensory Evaluation in Quality Control. Springer Science & Business Media. Naci, H., Ioannidis, J.P., 2015. How good is “evidence” from clinical studies of drug effects and why might such evidence fail in the prediction of the clinical utility of drugs? Annu. Rev. Pharmacol. Toxicol. 55, 169 189. Nagaich, U., Sadhna, D., 2015. Drug recall: an incubus for pharmaceutical companies and most serious drug recall of history. Int. J. Pharm. Invest. 5 (1), 13. Nusim, S. (Ed.), 2016. Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation. CRC Press, Boca Raton, FL. Onakpoya, I.J., Heneghan, C.J., Aronson, J.K., 2016a. Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review. BMC Med. 14 (1), 191. Onakpoya, I.J., Heneghan, C.J., Aronson, J.K., 2016b. Worldwide withdrawal of medicinal products because of adverse drug reactions: a systematic review and analysis. Crit. Rev. Toxicol. 46 (6), 477 489. O’Connor, T.F., Lawrence, X.Y., Lee, S.L., 2016. Emerging technology: a key enabler for modernizing pharmaceutical manufacturing and advancing product quality. Int. J. Pharm. 509 (1), 492 498. Patel, K.T., Chotai, N.P., 2011. Documentation and records: harmonized GMP requirements. J. Young Pharm. 3 (2), 138 150. Patricia, V.A., 2007. A FDA perspective on Quality by Design. Pharm. Technol. Sourcing Manage. 3 (12) ,http:// www.pharmtech.com/pharmtech/article/articleDetail.jsp?id 5 469915. (last accessed 20.08.17.). Poeran, J., Rasul, R., Suzuki, S., Danninger, T., Mazumdar, M., Opperer, M., et al., 2014. Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety. BMJ 349, g4829. Pramod, K., Tahir, M.A., Charoo, N.A., Ansari, S.H., Ali, J., 2016. Pharmaceutical product development: a quality by design approach. Int. J. Pharm. Invest. 6 (3), 129. Prasanthi, N.L., Sudhir, M., Jyothi, N., 2016. A review on polymorphism perpetuates pharmaceuticals. Am. J. Adv. Drug Deliv. 4 (5), 58 63. Rahul, M., Piyoosh, S., Tekade, M., Atneriya, U., Dua, K., Hansbroe, P.M., et al., 2017. Microsponge embedded tablet for sustained delivery of nifedipine. Pharm. Nanotechnol. 5, 192 202. Raphael, M.F., Breur, J.M., Vlasveld, F.A., Elbert, N.J., Liem, Y.T., Kon, M., et al., 2016. Treatment of infantile hemangiomas: therapeutic options in regard to side effects and adverse events a review of the literature. Expert Opin. Drug Saf. 15 (2), 199 214. Raz, I., 2013. Guideline approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care 36 (Suppl. 2), S139 S144. Ribeiro, M.L.F., 2013. Implementation of an Anti-Counterfeiting Device, .47 48. Roy, S., 2012. Quality by design: a holistic concept of building quality in pharmaceuticals. Int. J. Pharm. Biomed. Res. 3 (2), 100 108. Rozet, E., Marini, R.D., Ziemons, E., Boulanger, B., Hubert, P., 2011. Advances in validation, risk and uncertainty assessment of bioanalytical methods. J. Pharm. Biomed. Anal. 55 (4), 848 858. Ruan, J., Martin, P., Shah, B., Schuster, S.J., Smith, S.M., Furman, R.R., et al., 2015. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N. Engl. J. Med. 373 (19), 1835 1844. Sangshetti, J.N., Deshpande, M., Zaheer, Z., Shinde, D.B., Arote, R., 2017. Quality by design approach: regulatory need. Arab. J. Chem. 10, S3412 S3425. Santos, O.M.M., Reis, M.E.D., Jacon, J.T., Lino, M.E.D.S., Simo˜es, J.S., Doriguetto, A.C., 2014. Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farma´cia Popular Rede Pro´pria. Braz. J. Pharm. Sci. 50 (1), 1 24. Savjani, K.T., Gajjar, A.K., Savjani, J.K., 2012. Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012, 10. Schalk, I.J., Mislin, G.L., 2017. Bacterial iron uptake pathways: gates for the import of bactericide compounds. J. Med. Chem. 60, 4573 4576.

DOSAGE FORM DESIGN CONSIDERATIONS

770

21. IMPACT OF PHARMACEUTICAL PRODUCT QUALITY ON CLINICAL EFFICACY

Schmid, M.K., Bachmann, L.M., Fa¨s, L., Kessels, A.G., Job, O.M., Thiel, M.A., 2014. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br. J. Ophthalmol. pp.bjophthalmol-2014. Shahbaz, M., Srinivas, M., Harding, J.A., Turner, M., 2006. Product design and manufacturing process improvement using association rules. Proc. Inst. Mech. Eng. Part B: J. Eng. Manuf. 220 (2), 243 254. Shanafelt, T.D., Bradley, K.A., Wipf, J.E., Back, A.L., 2002. Burnout and self-reported patient care in an internal medicine residency program. Ann. Intern. Med. 136 (5), 358 367. Sharma, A., Houshyar, R., Bhosale, P., Choi, J.I., Gulati, R., Lall, C., 2014. Chemotherapy induced liver abnormalities: an imaging perspective. Clin. Mol. Hepatol. 20 (3), 317. Sharma, P.A., Maheshwari, R., Tekade, M., Tekade, R.K., 2015. Nanomaterial based approaches for the diagnosis and therapy of cardiovascular diseases. Curr. Pharm. Des. 21 (30), 4465 4478. Shea, B., Swinden, M.V., Ghogomu, E.T., Ortiz, Z., Katchamart, W., Rader, T., et al., 2014. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. J. Rheumatol. pp.jrheum-130738. Shirzad, H., Nasri, H., 2014. Toxicity and safety of medicinal plants. J. HerbMed Pharmacol. 2 (2), 21 22. Short, S.M., Cogdill, R.P., Drennen III, J.K., Anderson, C.A., 2011. Performance-based quality specifications: the relationship between process critical control parameters, critical quality attributes, and clinical performance. J. Pharm. Sci. 100 (4), 1566 1575. Sk, S., Viswanath, A., Srinivasa, P., 2013. Quality by design-novelty in pharmaceuticals. World J. Pharm. Res. 2 (5), 1409 1422. Sola, D., Rossi, L., Schianca, G.P.C., Maffioli, P., Bigliocca, M., Mella, R., et al., 2015. Sulfonylureas and their use in clinical practice. Arch. Med. Sci. 11 (4), 840. Srinivasa, A., Tosounidou, S., Gordon, C., 2017. Increased incidence of gastrointestinal side effects in patients taking hydroxychloroquine: a brand-related issue? J. Rheumatol. 44 (3), 398. Stark, J., 2015. Product lifecycle management. Product Lifecycle Management (Volume 1). Springer International Publishing, Cham, Switzerland, pp. 1 29. Tekade, R., Xu, L., Hao, G., Ramezani, S., Silvers, W., Christensen, P., Sun, X., 2014. A facile preparation of radioactive gold nanoplatforms for potential theranostic agents of cancer. J. Nucl. Med. 55 (suppl. 1), 1047-1047. Tekade, R.K., Maheshwari, R., Soni, N., Tekade, M., Chougule, M.B., 2017. Chapter 1 - Nanotechnology for the development of nanomedicine A2 - Mishra, Vijay. In: Kesharwani, P., Amin, M.C.I.M., Iyer, A. (Eds.), Nanotechnology-Based Approaches for Targeting and Delivery of Drugs and Genes. Academic Press. Thacker, A., Fu, S., Boni, R.L., Block, L.H., 2010. Inter-and intra-manufacturer variability in pharmaceutical grades and lots of xanthan gum. AAPS PharmSciTech 11 (4), 1619 1626. Thoorens, G., Krier, F., Leclercq, B., Carlin, B., Evrard, B., 2014. Microcrystalline cellulose, a direct compression binder in a quality by design environment—a review. Int. J. Pharm. 473 (1), 64 72. Turner, P.J., Gowland, M.H., Sharma, V., Ierodiakonou, D., Harper, N., Garcez, T., et al., 2015. Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012. J. Allergy Clin. Immunol. 135 (4), 956 963. Van Buskirk, G.A., Asotra, S., Balducci, C., Basu, P., DiDonato, G., Dorantes, A., et al., 2014. Best practices for the development, scale-up, and post-approval change control of IR and MR dosage forms in the current qualityby-design paradigm. AAPS PharmSciTech 15 (3), 665 693. Vinod, K., Diaz, V., 2015. Use of amniotic membrane graft in the surgical management of cicatricial ectropion associated with cetuximab therapy. J. Surgical Case Rep. 2015, 1. Wang, X., Song, Y., Su, Y., Tian, Q., Li, B., Quan, J., et al., 2016. Are PEGylated liposomes better than conventional liposomes? A special case for vincristine. Drug Deliv. 23 (4), 1092 1100. Waning, B., Montagne, M., McCloskey, W.W., 2001. Pharmacoepidemiology: Principles and Practice. McGrawHill, New York. Wilkins, K., Shields, M., 2008. Correlates of medication error in hospitals. Health Rep. 19 (2), 7. Woodcock, J., Wosinska, M., 2013. Economic and technological drivers of generic sterile injectable drug shortages. Clin. Pharmacol. Ther. 93 (2), 170 176. Stegemann, S. (Ed.), 2016. Developing Drug Products in an Aging Society: From Concept to Prescribing, vol. 26. Springer, Cham, Switzerland. World Health Organization and Stop TB Initiative (World Health Organization), 2010. Treatment of Tuberculosis: Guidelines. World Health Organization.

DOSAGE FORM DESIGN CONSIDERATIONS

FURTHER READING

771

World Health Organization, 2015. Guidelines for the Treatment of Malaria. World Health Organization. Wu, Y., Levons, J., Narang, A.S., Raghavan, K., Rao, V.M., 2011. Reactive impurities in excipients: profiling, identification and mitigation of drug excipient incompatibility. AAPS PharmSciTech 12 (4), 1248 1263. Yadav, A.V., Shete, A.S., Dabke, A.P., Kulkarni, P.V., Sakhare, S.S., 2009. Co-crystals: a novel approach to modify physicochemical properties of active pharmaceutical ingredients. Ind. J. Pharm. Sci. 71 (4), 359. Zaher, H., Rasheed, H., El-Komy, M.M., Hegazy, R.A., Gawdat, H.I., Halim, D.M.A., et al., 2016. Propranolol versus captopril in the treatment of infantile hemangioma (IH): a randomized controlled trial. J. Am. Acad. Dermatol. 74 (3), 499 505. Zaman, M., Adnan, S., Farooq, M., Aun, A., Yousaf, M.U., Naseer, A., et al., 2016. A comprehensive review on bioequivalence studies in human subjects. Br. J. Pharm. Res. 11, 2. Zattera, T., Londrino, F., Trezzi, M., Palumbo, R., Granata, A., Tatangelo, P., et al., 2017. Pemetrexed-induced acute kidney failure following irreversible renal damage: two case reports and literature review. J. Nephropathol. 6 (2), 43.

Further Reading FDA, Introduction to Medical Medical Device Recalls. ,https://www.fda.gov/downloads/Training/ CDRHLearn/UCM209281.pdf. (accessed 06.09.17). FDA, Drug Interactions: What You Should Know. ,https://www.fda.gov/drugs/resourcesforyou/ucm163354. htm. (accessed 07.09.17). Medina, C. (Ed.), 2003. Compliance Handbook for Pharmaceuticals, Medical Devices, and Biologics. CRC Press, Boca Raton, FL. Nichols, P., Copeland, T.S., Craib, I.A., Hopkins, P., Bruce, D.G., 2008. Learning from error: identifying contributory causes of medication errors in an Australian hospital. Med. J. Aust. 188 (5), 276 279. Patel, H., Parmar, S., Patel, B., 2013. A comprehensive review on Quality by Design (QbD) in pharmaceuticals. Development 4, 5. Recalls, Market Withdrawals, & Safety Alerts. ,https://www.fda.gov/Safety/Recalls/default.htm. (accessed on 10.07.17). Vlahovi´c-Palˇcevski, V., Mentzer, D., 2011. Postmarketing surveillance. Pediatric Clinical Pharmacology. Springer Berlin Heidelberg, pp. 339 351.

DOSAGE FORM DESIGN CONSIDERATIONS