Computer Access Controls

To ensure that individuals have the authority to proceed with data entry, data entry systems must be designed to limit access so that only authorized individuals are able to input data. Examples of methods for controlling access include using combined identification codes passwords or biometric-based identification at the start of a data entry session. Controls and procedures must be in place that are designed to ensure the authenticity and integrity of electronic records created, modified,...

Program Management Instructions Coverage

It is important to draw distinctions between a clinical laboratory, a clinical facility, and an analytical facility. A clinical laboratory generally uses blood and or urine to conduct medical screening or diagnostic tests such as complete blood counts (CBC), liver function tests alanine aminotransferase (ALT), aspartate aminotransferase (AST) or kidney function (blood urea nitrogen (BUN), creatinine clearance, etc.) tests. Clinical laboratories are usually certified under programs based on the...

Caco2 Drug Transport Assays

Drug absorption generally occurs either through passive transcellular or paracellular diffusion, active carrier transport, or active efflux mechanisms. Several methods have been developed to aid in the understanding of the absorption of new lead compounds. The most common ones use an immortalized cell line (e.g., Caco-2, Madin-Darby carine kidney (MDCK)) to mimic the intestinal epithelium. These in vitro models provide more predictive permeability information than artificial membrane systems...

DPK Approaches

The DPK approach is comparable to a blood, plasma, urine PK approach applied to the stratum corneum. DPK encompasses drug concentration measurements with respect to time and provides information on drug uptake, apparent steady-state levels, and drug elimination from the stratum corneum based on a stratum corneum concentration-time curve. When applied to diseased skin, topical drug products induce one or more therapeutic responses, where onset, duration, and magnitude depend on the relative...

Info

Root Mean Square Error 0.978185 CV 0.378775 Minimum detectable difference 0.2925 A.8. BIOANALYTICAL REPORT SPECIFIC INFORMATION REDACTED A.8.1. Introduction Metformin hydrochloride N,N-Dimethylimidodicarbonimidic diamide hydrochloride. Metformin hydrochloride is an oral antihyperglycemic drug used in the management of non-insulin-dependent diabetes mellitus. Metformin hydrochloride is not chemically or pharmacologically related to the oral sulfonylureas. The structural formula of metformin...

Hydrates

When solvate happens to be water, these are called hydrates wherein water is entrapped through hydrogen bonding inside the crystal and strengthens crystal structure and thereby invariably reduces the dissolution rate (Table 11). The water molecules can reside in the crystal either as isolate lattice where they are not in contact with each other, or lattice channel water where they fill space and metal coordinated water in salts of weak acids where meta ion coordinates with water molecule....

Offthe Shelf Software

While the FDA has announced that it intends to exercise enforcement discretion regarding specific Part 11 requirements for validation of computerized systems, persons must still comply with all predicate rule requirements for validation. It was suggested in the guidance for industry on Part 11 that the impact of computerized systems on the accuracy, reliability, integrity, availability, and authenticity of required records and signatures be considered when you decide whether to validate, and...

Rectal Administration

Some drugs are administered rectally either in suppository or in solution form, e.g., retention enema. The solution yield better absorption provided that they are retained for a sufficient length of time in the rectum. The suppositories are the most commonly used dosage forms for both local and systemic effect. Examples of drugs administered rectally for systemic action include aspirin, acetaminophen, indomethacin, diazepam, theophylline, prochlorperazine, cyclizine, promethazine, and...

Tables and Figures

Table 1.1 Final and Draft-Stage Biopharmaceutics Guidelines of the U.S. Food and Drug Administration Table1.2 Therapeutic Equivalence Code Classifications of the U.S. Food and Drug Administration Table 1.3 Factors Determining the Establishment of Bioequivalence Requirement by the Food and Drug Administration Table 1.4 Drugs with Potential Bioequivalency Problems Table 2.1 Data Requirement for Drug Approval in the United States Table 2.2 Classification of Active Ingredients According to Their...

Study Phase Phase II

Drugs taken within the wash out period_ 3. Alcohol consumption within the last 24 hours _ 4. Alcohol screening result Negative 5. Caffeine consumption within the last 24 hours (or as specified in the study protocol) (coffee, tea, cola, chocolate, etc) _ 6. Meals leftovers (see meal composition in the master file of the study) 6. Meals leftovers (see meal composition in the master file of the study)

Fed vs Fasted State

Feeding may either enhance or interfere with drug absorption, depending upon the characteristics of the drug and the formulation. Feeding may also increase the inter- and intrasubject variability in the rate and extent of drug absorption. The rationale for conducting each BE study under fasting or fed conditions should be provided in the protocol. Fasting conditions, if used, should be fully described, giving careful consideration to the PKss of the drug and the humane treatment of the test...

Intramuscular Administration

More than 50 of hospitalized patients receive intramuscular drug administration. The popularity of this route is due to the decreased hazard of administration when compared with the intravenous route. Large volumes of solution can be injected (2-10 mL) by this route, generally with less pain and irritation than is encountered with the subcutaneous route. Aqueous solution of drugs are usually absorbed from intramuscular administration sites within 10 to 30 minutes, but faster or slower...

Background

The bioequivalence (BE) review process establishes that the proposed generic drug is bioequivalent to the reference listed drug, based upon a demonstration that both the rate and the extent of absorption of the active ingredient of the generic drug fall within established parameters when compared to that of the reference listed drug. The Food and Drug Administration (FDA) requires an applicant to provide detailed information to establish bioequivalency. Applicants may request a waiver from...

Analytical Data And Operations

Information required by this section must be obtained with the assistance of a qualified analyst from the field and or a reviewer in GBIB with expertise in the type of analysis used in the BE study under review. At random, compare the analytical source data with data provided in the inspection assignment for accuracy of transference and for scientific soundness bearing on the validity of the study. Analytical source data are codes used to blind samples data establishing the sensitivity,...

Data Audit

In addition to the procedures outlined above for evaluating the overall GLP compliance of a firm, the inspection should include the audit of at least one completed study. Studies for audit may be assigned by the Center or selected by the investigator as described in Part III, A. The audit will include a comparison of the protocol (including amendments to the protocol), raw data, records, and specimens against the final report to substantiate that protocol requirements were met and that findings...

Bibliography

Bhattycharyya L, Dabbah R, Hauck W, Sheinin E, Yeoman L, Williams R. Equivalence studies for complex active ingredients and dosage forms. AAPS J 2005 7(4) E786-812. Chen ML, Shah V, Patnaik R, et al. Bioavailability and bioequivalence an FDA regulatory overview. Pharm Res 2001 18(12) 1645-50. Devine JW, Cline RR, Farley JF. Follow-on biologics competition in the biopharmaceutical marketplace. J Am Pharm Assoc (Wash DC) 2006 46(2) 193-201 (quiz 202-4). Fareed J, Leong WL, Hoppensteadt DA, et al....

Summary

This study was performed to investigate the bioequivalence of cyclosporine between a generic test product Sigmasporin Microoral, 100 mg cyclosporine per 1 mL solution Gulf Pharmaceutical Industries (Julphar), U.A.E. and reference product (Sandimmun Neoral, 100 mg cyclosporine per 1 mL solution Novartis Pharma, Switzerland). The clinical protocol called for 30 healthy volunteers, at least. The subjects received 1 mL of each product, Sigmasporin Microoral solution and Sandimmun Neoral solution...

Sites and Duration of Application

The BE study should include measurements of drug uptake into the stratum corneum and drug elimination from skin. Each of these elements is important to establish BA and or BE of two products, and each may be affected by the excipients present in the product. A minimum of eight sites should be employed to assess uptake elimination from each product. The time to reach steady state in the stratum corneum should be used to determine timing of samples. For example, if the drug reaches steady state...

Lipophilizing Modifications

Increasing lipid solubility through chemical modifications is exemplified by doxycycline, a derivative of tetracycline. This compound is more efficiently absorbed from the intestine than tetracycline partly because of better lipid solubility and partly because of a decreased tendency to form poorly soluble complexes with calcium and phosphate. This facilitated absorption decreases the risk of disturbances in the intestinal flora and intestinal superinfection. Chemical TABLE 1 Examples of...

Be Testing Report Summary

Application Sponsor (if any) 5. Location where testing performed a. Clinical Facility Name Address 6. Responsible Official (Recipient of Notice of Inspection) a. Name and Title 7. Person receiving FDA-483 (if issued) a. Name and Title 9. Number of subjects in clinical test 10. Status of clinical testing 11. Sample Collection Sample Lot - In the 1970s, FDA inspections of nonclinical laboratories revealed that some studies submitted in support of the safety of...

Additional Considerations

When requesting a BCS-based waiver for in vivo BA BE studies for IR solid oral dosage forms, applicants should note that the following factors can affect their request or the documentation of their request. Excipients can sometimes affect the rate and extent of drug absorption. In general, using excipients that are currently in FDA-approved IR solid oral dosage forms will not affect the rate or extent of absorption of a highly soluble and highly permeable drug substance that is formulated in a...

Acidity

Gastric emptying is also retarded by increased acidity of gastric fluids. The use of antacid compounds increases gastric emptying rates. An interesting application of this property is the administration of l-dopa with sodium bicarbonate. Since l-dopa decomposes in the stomach, its administration with sodium bicarbonate increases its bioavailability due to decreased decomposition in the stomach and the result of both decreased acidity and increased emptying of the contents into the intestine....

Bioequivalence and Systemic Exposure Models

Screening drug molecules for suitability for use in humans is often subjected to certain basic toxicity or workability solutions to reduce the cost of screening. The human body must be able to remove the drug in a reasonable time. Drug CL is an intrinsic parameter however, body CL (extent of drug removal) is dependent on cardiac output and the overall extraction ratio. Body clearance (plasma, blood) Q X ER The ER is the extraction ratio that ranges from 0 to 1, and the cardiac output is...

Trial Management Data Handling and Record Keeping

5.5.1 The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports. 5.5.2 The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify,...

Contents of the Investigators Brochure

The IB should contain the following sections, each with literature references where appropriate An example of the Table of Contents is given in Appendix 2. A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product. A brief introductory...

Principles of Software Validation

Whereas it is unlikely that a BE laboratory personnel will be involved in the validation of software more than testing it at the IQ OQ and PQ levels, it is important to understand how software is validated when requiring this certification from the vendors. Software quality assurance needs to focus on preventing the introduction of defects into the software development process and not on trying to test quality into the software code after it is written. Software testing is very limited in its...

Intestinal Transit

The residence time in the intestine has a direct bearing on the amount of drug absorbed, however, absorption may be reached if the drug is unstable in intestinal fluids or binds irreversibly to the intestinal contents. For dosage forms where the drug is released only in the small intestine, e.g., enteric coated forms intestinal transit times are of utmost importance. The peristaltic and mixing movements of intestine are also important in affecting the dissolution of the drug. Even though food...

Molecular Size

Large organic molecules have a smaller aqueous solubility than smaller molecules, this being due to interactions between the nonpolar groups and water, i.e., solubility is dependent on the number of solvent molecules that can pack around the solute molecule. Poorly soluble compounds represent an estimated 60 of compounds in development and many major marketed drugs. It is important to measure and predict solubility and permeability accurately at an early stage, and interpret these data to help...

Equivalence Documentation For Marketing Authorization

Pharmaceutically equivalent multisource pharmaceutical products must be verified to be therapeutically equivalent to one another in order to be considered interchangeable. Several test methods are available to assess equivalence, including Comparative bioavailability (BE) studies, in which the active drug substance or one or more metabolites are measured in an accessible biologic fluid such as plasma, blood, or urine Comparative pharmacodynamic (PD) studies in humans Comparative clinical trials...

Informed Consent of Trial Subjects

4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB IEC's written approval favorable opinion of the written informed consent form and any other written information to be provided to subjects. 4.8.2 The written informed consent form and...

Type Of Food

The type of food will affect the stomach emptying rate significantly. For example, fats decrease the rate proteins affect a lesser decrease and carbohydrates retard gastric emptying the least. A fatty meal can therefore retard absorption rates of the drug and delay the onset of action. However, with such water-insoluble drugs as griseofulvin the absorption can be increased as a result of retarded gastric emptying. The reason is that griseofulvin passes slowly to the small intestine, and...

Nasal Administration

The nasal cavity provides and ideal opportunity for the delivery of drugs. The nasal mucose has high vascularity and offers very little formability of local biotransformation. The pH of the surface is shown 7.2 and drugs are generally absorbed by passive diffusion based on their lipid solubility. A number of drugs are administered intranasally for their local affects such an antibiotics, decongestants, and antihistamines. The systemic delivery has generally been limited to only a few...

Pulmonary Administration

Drugs can be introduced into the pulmonary system as gases or in aerosol forms. An almost instantaneous absorption can be expected due to the extremely large surface area available for absorption. The primary mechanism of absorption is passive diffusion but the lipid solubility tends to play a smaller role than in gastrointestinal absorption. The main limiting step in the utilization of this route has been the need to design dosage forms which accurately deliver the drugs. Most of these drugs...

Quality Control Samples

The purpose of quality control (QC) samples is to assure that the complete analytical method, sample preparation, extraction, clean-up, and instrumental analysis perform according to acceptable criteria. The stability of the drug in the text matrix for the QC samples should be known and any tendency for the drug to bind to tissue or serum components over time should also be known. Drug free control matrix, e.g., tissue, serum, etc., that is freshly spiked known quantities of test drug, should...

Pharmacologic Evaluation of Bioavailability

The estimations of bioavailability discussed above are based on plasma and or urine levels of the drug and or its biotransformation products. It is understood in these calculations that these concentrations relate in some manner to the pharmacologic or clinical response of the drug. Ideally, therefore, it is desirable to measure bioavailability as a function of pharmacologic or clinical effect. In order to do so, a specific and discriminating test is needed. Some quantitative endpoint must be...

Dpk Be Study Protocol Protocol and Subject Selection

Healthy volunteers with no history of previous skin disease or atopic dermatitis and with a healthy, homogeneous forearm (or other) skin areas sufficient to accommodate at least eight treatment and measurement sites (time points) should be recruited. The number of subjects to be entered may be obtained from power calculations using intra- and intersubject variability from the pilot study. Because skin stripping is highly sensitive to specific study site factors, care should be taken to...

Percutaneous Administration

The absorption of drugs through the skin should be a difficult matter since the function of the skin is to act as a barrier between the outside environment and the vulnerable tissues under the skin. Yet drugs are absorbed, sometimes quite efficiently, from the skin. A major function of skin is to retard the diffusion and evaporation of water from within the body, except at the sweat glands. The stratum corneum, also known as the horny layer, which is densely packed with keratin, is responsible...

Intravenous Administration

The direct administration of drugs into veins is the only route where bioavailability considerations are not relevant. This route provides an almost instantaneous response with controllability of the rate of drug input into the body. This route is especially suitable for those drugs which cannot be absorbed adequately from the gastrointestinal tract or tissues depots (e.g., intramuscular administration) or where there is a significant first pass effect upon oral administration. The drugs which...

Biowaiver Courier Ma Gujarati Natak

A flexible technology for modified release of drugs multi layered tablets. J Control Release 2004 97(3) 393-405. Abrams J. Glyceryl trinitrate (nitroglycerin) and the organic nitrates. Choosing the method of administration. Drugs 1987 34(3) 391-403. Aldridge MA, Ito MK. Colesevelam hydrochloride a novel bile acid-binding resin. Ann Pharmacother 2001 35(7-8) 898-907. Atkins PJ. Dry powder inhalers an overview. Respir Care 2005 50(10) 1304-12 (discussion 1312). Bach M, Lippold...

Performance And Validation Of The Skin Stripping Technique

DPK studies should include validation of both analytical methods and the technique of skin stripping. Since the DPK approach involves two components of validation sampling and analytical method , overall DPK variability may be greater than with other methodologies. For analytical methods, levels of accuracy, precision, sensitivity, specificity, and reproducibility should be documented according to established procedures. Although the forearm, back, thigh, or other part of the body can be used...

Polymorphism

Both organic and inorganic pharmaceutical compounds can crystallize into two or more solid forms that have the same chemical composition and is called as polymorphism. Polymorphs have different relative intermolecular and or interatomic distances as well as unit cells, resulting in different physical and chemical properties such as density, solubility, dissolution rate, bioavailability, etc. When crystal structure contains solvents or water these are often called as psudopolymorphs with...