In Aspirin Tablets Magnesium Stearate Won't Be Used As a Lubricant Why?

                                    

In Aspirin Tablets Magnesium Stearate Won't Be Used As a Lubricant Why?

1.       Stearate salts reacts with aspirin to form corresponding salts of aspirin (especially calcium and magnesium salts), resulting increased solubility of aspirin and establishing a higher pH. pH change may be responsible for the stearate induced decomposition and this will affect the stability of the product.

2.      When magnesium stearate is used as a lubricant in aspirin formulation, it will affect the powder flow and content uniformity of the tablet.

DISPERSIBLE TABLETS

                                                      


Many medicines are only available in adult strength; therefore the administration of accurate dosage for children is critical. The adjustment of adult formulations to paediatric dosage is often done by cutting or crushing tablets, opening the capsules and using the powder to make a liquid, diluting concentrated preparations or, using injections orally, etc.As a direct consequence, children are often given formulations that have not been developed for them. This practice can compromise the efficacy and safety of the treatment.Paediatric medicines must allow accurate administration of the dose to children of varying age and weight.

Small-volume liquid medicines are appropriate for use in the younger age groups.But some drugs (ex.antibiotics) are unstable in liquid media,so they are available in solid forms.Children less than 5 years of age usually have problems with swallowing tablets and capsules (i.e. dysphagia).Dysphagia may be overcome by developing solid dosage forms (dispersible tablets) to be dissolved, dispersed or mixed with food, milk or water prior to administration.Dispersible tablets are a convenient formulation for infants, toddlers and pre-school children.

Dispersible tablets are uncoated or film-coated tablets that can be dispersed in liquid before administration giving a homogenous dispersion.Dispersible tablets usually disintegrate within three minutes when put in water or a small amount of breast milk.

Advantages of dispersible tablets over conventional dosage forms

• Qucker onset action compared with conventional tablets because of improved bioavailability.

• Suitable for children and elderly persons with swallowing difficulties (Dysphagia)

• More convenient for API's with insufficient stability in water.

• More easy for transportation (less volume,less weight)

• Dispersble tablets remain solid until administration. This aids the stability of the pharmaceutically active agent, the dose accuracy, and storage of the tablets.

Dispersible tablets have less physical resistance than regular tablets; they are more sensitive to moisture and may degrade at higher humidity conditions. Each tablet must be protected from the ambient humidity.The dispersible tablets should not be divided or chewed.Dispersible tablets must be used immediately after removal from the blister packaging. Their stability outside of the blister cannot be guaranteed.

DRY SYRUPS

                               
A number of drugs are unstable in an aqueous environment, even when exposed for a short duration,so they are supplied in solid/dry form.Traditional dosage forms such as pills and capsules lack the dosing flexibility required in paediatric use and dysphagic conditions.Dry syrup preparations provides a solution for this delima. In dry syrup, drug is distributed in dry form and is converted in liquid form by adding (reconstitution) water. The principal advantage of this dosage form is that it overcomes the problem of instability in solution(viscosity changes,crystal growth,caking etc.).Powders for reconstitution are attractive over liquid oral dosage forms because of their compactness, which makes them more convenient for storage and transport.

Dry syrups are preparations consisting of solid, loose, dry particles of varying degrees of fineness. They contain one or more active ingredients, with or without excipients and, if necessary,authorized colouring agent and flavouring substances. They are generally administered in or with water or another suitable liquid. They may also be swallowed directly. They are presented as singledose or multidose preparations.Most oral suspension use tap water for reconstitution unless or otherwise specified.Most of the reconstituted suspnesion won't be stable for a long time.It shall not be used after specified time mentioned in the label.Most of the antibiotics have a short shelf life in liquid medium so they are often supplied as dry syrups. 
Reconstitution, a pharmaceutical prerequisite for drysyrups, has direct implications on drug concentration, making it a critical parameter. Numerous intrinsic and extrinsic parameters affect the time and reproducibility of reconstitution of powders. Identification and control of these parameters during product development can reduce batch-to-batch variability in reconstitution time and provide confidence among the end users. A short and reproducible reconstitution time will also save the precious time and dose variability.

TEMPERATURE MAPPING IN PHARMACEUTICALS

Temperature Mapping is the process of recording and mapping the temperature in a 3 dimensional space. Temperature won't be the same everywhere,even it is in a small fridge, large cool room, freezer or warehouse and can vary by as much as 10°C from one location to another.Temperatures in the corners will most likely be different to the centre of the space being measured.

There are also "specific areas" within the cool room where the temperature also will differ such as: next to the cooling fans where the temperature will be at its coldest or close to the doors where it likely to be at its warmest.

Temperature Mapping and Temperature Monitoring are integral to the storage of pharmaceuticals because drug efficacy relies on good storage conditions.

In Pharmaceutical industry temperature mapping is done for Autoclaves
Dry Heat Sterilizers
ETO Chambers
Stabilty chamber
Incubators
Holding areas- warehouse


The purpose of temperature mapping is to ensure that all areas of the process equipment or storage area achieve the required temperature. The outcome of the test is a temperature map defining the cold spot of the process equipment or storage area.

Warehouse Temperature Mapping
Drug manufacturers are deeply concerned about consumer safety, product quality, and FDA compliance.Inadequately controlled environments can lead to ineffective and spoiled medicines.Most product warehouses have limited environmental control. Packaging obviously protects products against contamination and degradation from light, but the contents remain vulnerable to temperature and, in some cases,humidity. Warehouses for pharmaceutical raw materials and finished product must be maintained at controlled temperature and humidity.

There's increased emphasis by regulators on compliance with GMP requirements for controlled temperature storage requirements.


Clause 3.19 of the PIC/S GMP guide states:
"Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored."

PIC/S doesn't offer much advice on what this means in practice. UK Guidance on Wholesale Distribution Practice, states:

"Large commercial refrigerators and walk-in cold rooms should be monitored with an electronic temperature-recording device that measures load temperature in one or more locations, depending on the size of the unit. Portable data-loggers that can be downloaded onto a computer may be used instead of a fixed device. Records should be checked daily. Internal air temperature distribution should be mapped on installation in the empty and full state and annually thereafter under conditions of normal use. Products should not be stored in areas shown by temperature mapping to present a risk (e.g. in the airflow from the refrigeration unit). Condensate from chillers should not be collected inside the unit.

All warehouses should be temperature mapped to determine the temperature distribution under extremes of external temperature. Mapping should be repeated every two to three years and after any significant modification to the premises, stock layout, or heating system.
Even in an open warehouse design temperature and humidity is not usually constant from one spot to another because:
1) Areas near the ceiling or exterior walls may stay warmer or cooler in response to outside temperatures.
 2) As warm air rises, temperatures stratify;
3) Temperatures are higher near heaters, and especially so if fans are undersized or placed in such a way that they cannot completely mix the air;
4) Hot spots are created by racking, shelving and pallet storage areas that obstruct air circulation; and
5) Frequently opened doors affect temperatures.

These and other factors may create substantial temperature differences from floor to ceiling and within building zones. In fact, variations of several degrees are common in large storage areas.Mapping of a warehouse is required to assure proper conditions are maintained during all hours of operation and seasons. Two or more mappings may be required to account for seasonal conditions (i.e. winter & summer).

　
Temperature Mapping vs Temperature Monitoring And Calibration


Temperature controlled storage areas in GMP facilities are usually continuously monitored by temperature probes . These are routinely calibrated, which might suggest that this all that is needed to meet regulatory requirements.

But temperature mapping is very different from calibration/routine monitoring. One of the key differences is the number of points the temperature is measured at in the temperature controlled area.

A temperature mapping exercise is expected to collect the following information:
* The impact of interventions (door openings / power failures, etc.),
* Identification of hot and cold spots,
* Variation of temperature at a single point,
* Temperature variation across the area,
* Length of time of any temperature excursions.


To record all this information effectively, each temperature mapping exercise should be governed by a protocol detailing:
* Selection of testing dates, with consideration to seasonal effects on the temperature controlled area,
* Number of probes to be used and justifications,
* Map of probe locations and justifications, including potential hot and cold spots,
* Duration of the exercise,
* What constitutes "normal use" and therefore levels of stock in the area that are to be used,
* Calibration requirements (pre and post),
* Acceptable number of probe failures,
* Acceptable limits for temperature excursions (which may be product dependent),
* Types of data to be generated,
* Reporting requirements.

Mapping is not a one-time job, but an ongoing process that takes into account changes in seasons, HVAC/R modifications, warehouse layout modifications and any other significant changes to the warehouse environment.

Proper organization and documentation are critical in maintaining compliance and consistency.

Important points should be considerd during Thermal Mapping

Thermocouples/data loggers should be checked before and after a validation study.
Temperature recording probes should have an accuracy of at least +/- 0.5 °C.

Warehouses should be temperature mapped in the empty and full states to determine the temperature distribution under extremes of external temperature. The mapping exercise should be performed both during summer and winter in order to assess worst case scenarios, as extremes of temperature may adversely affect the temperature distribution within the warehouse storage area.

Temperature monitoring should be conducted within a normal working day rather than on a weekend as the internal temperature of the space will vary depending on how many times the coolroom or warehouse doors are opened and closed.
Temperature mapping should be repeated after significant modification to the premises, changes in stock layout or changes to the heating system. Due considerations should also be given where the practice of turning off heating systems overnight or over weekends is employed. In general, medicinal products should not be stored next to sun facing windows, at high levels in poorly insulated stores, at high levels under or near fluorescent lights, or next to heaters. Medicinal products should not be stored in areas shown by the temperature mapping to be unsuitable.

Step 1 – Determine Critical Mapping Points

Problem Locations:Large open spaces present a considerable challenge when working to maintain a consistent temperature or temperature/humidity level. Problem spots include:

*Areas near the ceiling or exterior walls may stay warmer or cooler in response to temperatures outside.
* Temperature levels stratify due to the fact that warmer air rises.
* Temperatures will tend to be higher near heaters, if fans are undersized or improperly placed they  will be incapable of mixing the heated air effectively.
* Racking, shelving and pallet storage areas may create "hot spots" by obstructing air circulation.
* Doors that are left open will affect temperature conditions.

Additional Locations:In addition to problem spots logger placement is also critical for the following locations:
*HVAC outputs,
*Exits to unconditioned spaces (loading docs and staging areas),
*Outside (to compare outside temperatures to internal temperatures),
*High, medium and low locations in the general storage area.

Spacing:
Data loggers need to be strategically placed within the 3 dimensional space to map temperatures along a horizontal, vertical and depth plain as well as in locations that are likely to have temperature variations.Studies have shown that a spacing of every 100 to 300 feet in an open warehouse plan, without walls to block airflow, is adequate enough to accurately represent readings that are meaningful. A distance of greater than every 300 feet may yield data that does not accurately reflect conditions in the warehouse space, while spacing data loggers closer than every 100 feet will result in extra data that adds no value while creating extra work.

Step 2 – Determining Sample Frequency:The key to determining sample frequency is to not take too many or too few samples. Too many samples will create too much data making analysis cumbersome and difficult. Too few samples will not adequately represent changes in the warehouse environment. In most warehouses, one temperature or temperature and humidity sample every 15 minutes (for aperiod of one to two weeks) should adequately evaluate temperature trends.

Step 3 – Establish Data Logger Criteria and Select:Temperature and Temperature/Humidity Data Loggers come with many features. The goal is to select the data logger that will most effectively monitor your warehouse. Key features you should consider are:

Data Capacity: Data Capacity determines how many readings or sample points can be taken by a logger before memory is full. The more sample points a logger has, the more readings it can store.
Sample Rate: The frequency in which samples are taken. The logger should feature user selectable sample rates.
Monitoring Range and Accuracy: Be sure to select a data logger with a temperature range that can monitor temperatures even in the most extreme of cases. +/-2oF and +/-2% RH should be adequate for most warehouse mapping situations. For refrigerated storage areas or locations requiring tighter tolerances, data loggers with an accuracy of +/-.5 oF should be selected.
Size: Make sure the logger will fit in your selected locations.
Battery Life: Make sure the battery life is long enough to last between mapping sessions.
Calibrations: The data loggers should be calibrated at least every 12 months.
Software: Make sure the data logger software is easy to use.

Step 4 – Place Data Loggers at Pre Determined Points:Be sure to document the location of each data logger and label each data logger to ensure that it is repeatedly placed in the same location.

To ensure consistency practice the following rules:
Using the data logger software, name each logger by its location,
Label the outside of each logger by its location,
Label the exact spot where the data logger should be placed by the data logger’s location name,
Create a physical map with all data loggers marked by name.

Step 5 – Retrieve and download Logged Data: Once the loggers have been placed and data has been collected, collect the data loggers and transfer the logged data computer.

The logged data can be exported to Excel where Mean Kinetic Temperature can be calculated.

Mean Kinetic Temperature is a calculated fixed temperature that simulates the effects of temperature variations over a period of time. It expresses the cumulative thermal stress experienced by a product at varying temperatures during storage and distribution.In addition to calculating MKT it is also recommended that Min and Max temperatures should be monitored carefully and that the location and the time of day at which they occur should be recorded. Any trends should be investigated.

Step 6 - Document Processes and Repeat: After completion of first mapping, be sure to place the data loggers back in their original locations throughout the warehouse and make sure to document each and every step used.

Step 7 – Data Logger Maintenance and Calibrations:Over time the most robust data loggers can drift causing inconsistencies in recorded data thus requiring regular calibration in order to ensure accurate readings.

It is recommended that each data logger be calibrated at least every 12 months. In addition, it is prudent to request before and after readings when calibrating each data logger so corrections can be made to previously logged and mapped data.

Best practice recommends sending the data logger to a NIST certified calibration facility, and to the original manufacturer for calibration whenever possible.

Step 8 – Remediation:Results has to be evaluated to fix any trouble spots that show up in the calculations.

The graphs and charts and on-site observations become part of a complete report that notes any undesirable temperature or humidity patterns and recommends potential remedies.The report contains copies of all sensor calibration certificates, questionnaires, and other information used to complete the study. If the mapping study indicates undesirable conditions, facility owners can take a wide range of measures, depending on the problems’ severity. They include:

• Removing product from problem areas (such as hot spots near ceilings).

• Changing work practices (such as keeping doors open or closed).

• Changing racking or shelving configurations. Repositioning racks or shelving to improve air circulation.

• Changing the location of heating devices.

• Adding air conditioning.

• Improving ventilation.

• Installing more or larger-capacity fans.

• Adding humidification or dehumidification.

• Installing an HVAC control system.

Temperature mapping can be an extremely powerful tool to aid in regulatory compliance and create possible cost savings via implemented improvements and efficiencies. The key is to carefully analyze the warehouse space to ensure proper placement of data loggers, document logger locations and mapping processes.

ANTIFUGAL DRUGS AND PHARMACOLOGICAL ACTIVITIES

                               


Terbinafine -Terbinafine hydrochloride (Lamisil) is a synthetic allylamine antifungal.Terbinafine inhibits ergosterol synthesis by inhibiting the fungal squalene monooxygenase (squalene 2,3-epoxidase), an enzyme that is part of the fungal cell wall synthesis pathway.Terbinafine hydrochloride is used for the treatment of dermatophyte infections.



Itraconazole-is a triazole antifungal agent that inhibits cytochrome P-450-dependent enzymes resulting in impairment of ergosterol synthesis. It has been used against histoplasmosis, blastomycosis, cryptococcal meningitis & aspergillosis.Itraconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 α-demethylation via the inhibition of the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell wall synthesis. The subsequent loss of normal sterols correlates with the accumulation of 14 α-methyl sterols in fungi and may be partly responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition.



Clotrimazole-is an imidazole derivative with a broad spectrum of antimycotic activity. It inhibits biosynthesis of the sterol ergostol, an important component of fungal cell membranes. Its action leads to increased membrane permeability and apparent disruption of enzyme systems bound to the membrane.It is used for the local treatment of oropharyngeal candidiasis and vaginal yeast infections, also used in fungal infections of the skin such as ringworm, athlete's foot, and jock itch



Ciclopirox- is a broad-spectrum antifungal medication that also has antibacterial and anti-inflammatory properties. Its main mode of action is thought to be its high affinity for trivalent cations, which inhibit essential co-factors in enzymes.



Fluconazole-is a synthetic antifungal agent of the imidazole class, is used to treat vaginal candidiasis. It inhibits the fungal lanosterol 14 alpha-demethylase which thereby prevents the formation of ergosterol which is an essential component in the fungal cell membrane



Ketoconazole-is an imidazole antifungal agent.It is used for treating candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.Ketoconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability. Other mechanisms may involve the inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast transformation to mycelial forms, inhibition of purine uptake, and impairment of triglyceride and/or phospholipid biosynthesis.



Miconazole-is An imidazole antifungal agent.It is used either on the skin or in the vagina for fungal infections. Miconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Miconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.

What is DMF/ Drug Master File

Drug Master File (DMF) : is a document prepaired by a pharmaceutical manufacturer and submittedsolely at its discretion to the appropriate regulatory agency.DMF contains confidential and factual information about facilities, processes(includes drug product's chemistry, manufacture, stability, purity, impurity profile etc.) or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.DMF helps the manufacturer to keep relevant information secret and at the same time to sell the product to different customers using this drug within there final application.The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or disapproved. Technical contents of a DMF are reviewed only in connection with the review of an IND, NDA, ANDA, or an Export Application.

DMF contains complete information on an Active Pharmaceutical Ingredient (API) or finished drug dosage form. In Europe it is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) and in US it is known as US-Drug Master file (US-DMF).

Note:EDMF is the old name of Active Substance Master File (ASMF)

DMF’s are mostly prepared following the rules of Common Technical Documentation (CTD).

Prerequisites





Production process is well established and fixed in writing (Master production instructions).
Specifications of raw materials as well as of the final product are defined including specification of packaging material.
Inprocess controls, sampling points and procedures are clearly outlined.
Critical process steps are validated, equipment is qualified.
Analytical methods are validated.
Impurity profile is established.
Stability program is set up and first data are available.
Basic GMP requirements are fullfilled.
Data required for the CTD are

General Information
Nomenclature
Structure Description
General Properties
Manufacture
Manufacturer(s)
Description of manufacturing process and process controls
Control of materials
Controls of critical steps and intermediates
Process validation and/or evaluation
Manufacturing process development.
Characterisation
Elucidation of structure and other characteristics
Impurities
Control of drug substance
Specification
Analytical Procedures
Validation of analytical procedures
Batch analyses
Justification of Specification
Reference Standards or Materials
Container Closure System
Stability


US-DMF

In United states DMFs are submitted to the FDA.The main objective of the DMF is to support regulatory requirements and prove the quality,safety and efficacy of the medicinal product.

In US there are five types of DMF's:
Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel

Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product

Type III Packaging Material

Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation

Type V FDA Accepted Reference Information

Type I
 Manufacturing Site, Facilities, Operating Procedures, and PersonnelA Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout.

The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful.

A diagram of major production and processing areas is helpful for understanding the operational layout. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique.

A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful.

　

Type IIDrug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug ProductA Type II DMF should, in general, be limited to a single drug intermediate, drug substance, drug product, or type of material used in their preparation.It Summarize all significant steps in the manufacturing and controls of the drug intermediate or substance.

Type IIIPackaging MaterialEach packaging material should be identified by the intended use, components, composition, and controls for its release. The names of the suppliers or fabricators of the components used in preparing the packaging material and the acceptance specifications should also be given. Data supporting the acceptability of the packaging material for its intended use should also be submitted.

Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their PreparationEach additive should be identified and characterized by its method of manufacture, release specifications, and testing methods.

Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document.

Type VFDA Accepted Reference InformationFDA discourages the use of Type V DMF's for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMF's. If any holder wishes to submit information and supporting data in a DMF that is not covered by Types I through IV, a holder must first submit a letter of intent to the Drug Master File Staff (for address, see D.5.a. of this section). FDA will then contact the holder to discuss the proposed submission.

General Requirements for Filling TypeI,II,III,IV,V DMF's
Type II, Type III, and Type IV DMF's should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws.

Stability study design, data, interpretation, and other information should be submitted.

A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference.

EDMF

In Europe DMFs are submitted to EMEA.The main objective of the Active Substance Master File (ASMF) procedure, commonly known as the European Drug Master File (EDMF), is to allow valuable confidential intellectual property or 'know-how' of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or marketing authorisation (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. Competent Authorities/EMEA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product.

The scientific information in the EDMF should be physically divided into two separate parts, namely the Applicants Part (AP) and the Restricted Part (RP). The AP contains the information that the EDMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the EDMF holder regards as confidential.

It is emphasized that the AP is still a confidential document that cannot be submitted by anyone to third parties without the written consent of the EDMF holder. In all cases the AP should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specifications for the active substance to control the quality of this active substance for use in the manufacture of a specified medicinal product. The RP may contain the remaining information, such as detailed information on the individual steps of the manufacturing method (reaction conditions, temperature, validation and evaluation data of critical steps) and the quality control during the manufacture method of the active substance.

The EDMF procedure can be used for the following active substances (except biological active substances)

A. New active substances

B. Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or the pharmacopoeia of an EU Member State

C. Pharmacopoeial active substances included in the Ph. Eur. or in the pharmacopoeia of an EU Member State

DMF (Drug Master File), CoS (Certificate of suitability) as well as CMC (Chemical Manufacturing and Control Documentation) are used for one and the same intention – to give evidence, that the drug substance (API – Active Pharmaceutical Ingredient) is suitable for its intended use and that the manufacturing process is well established and controlled. Content of DMF, CoS, and CMC are nearly equal. There are only differences in the kind of document preparation (forms to use) and the authority you have to contact (USDMF FDA; EDMF EMEA; CoS EDQM; CMC national bodies). Therefore above mentioned procedure is nearly equal for all the three types. Especially CoS does not replace an approval process. Approval authorities can require more information even if CoS is available.

Expanded access program (EAP)

Title 21 part 313.34 of the Code of Federal Regulations provides for use of unapproved drugs to treat patients with serious or immediately life-threatening diseases ineligible for clinical trials and without available alternative therapy. EAPs can provide drugs to individual patients under "single patient Investigational New Drug (IND)" and to larger numbers under "treatment IND". The criteria for drug use under "Treatment IND" include a life threatening disease, no other treatments available, preliminary evidence of efficacy, ongoing or completed definitive clinical trials, marketing approval has been pursued, and absence of interference with the registration process. EAPs are implemented while sponsors are actively pursuing marketing approval. Reasonable evidence of clinical usefulness for the indication and sufficient safety information from ongoing or completed trials are required. EAPs are voluntarily initiated by the drug sponsor. FDA and IRB approvals and safety monitoring are required. EAPS can be used for a widerange of diseasesincluding AIDS,cancer,rare diseases and cardiovascular diseases.


Medical professionals use the term "compassionate use" to refer to the treatment of a seriously ill patient using a new, unapproved drug when no other treatments are available. Drugs that are being scientifically tested but have not yet been approved by the US Food and Drug Administration (FDA) are called investigational drugs. Being able to use one of these drugs when you are not in a clinical trial has many names, but is most commonly referred to as compassionate use.

Since 1987, the FDA has had rules in place that have enabled patients, under specific circumstances, to access drugs or biologics that are still in development for treatment purposes. These expanded access program rules were amended in 2009 by the FDA.

The regulations include the following:

Criteria that must be met in order to authorize the expanded access use
Requirements for expanded access submissions
Safeguards to protect patients and the clinical trial process
The regulations also include general criteria for granting expanded access:

The patient must have a serious condition or disease for which there is no comparable alternative therapy available
The patient must be unable to participate in a clinical trial
The potential benefit must outweigh the potential risk of using the treatment
The drug manufacturer or supplier must agree to provide the drug and necessary supporting regulatory information
An Institutional Review Board (IRB) must approve the treatment plan
There should be no impact on the completion of a clinical trial

EAPs can provide drugs to individual patients under "single patient Investigational New Drug (IND)" and to larger numbers under "treatment IND".

Expanded access
A company sponsoring a drug in the late stages of drug development, such as Phase III clinical trials, can offer expanded access programs for patients who are not able to enroll in a clinical trial. The FDA generally approves these EAPs if the drug has shown that it works at least somewhat to treat a specific disease in the clinical trials that are being done.

Single patient access
Patients who don’t qualify for either clinical trials or an expanded access program (if one exists) may be able to get the unapproved new drug by applying for single patient access.

In this case, the patient’s doctor must first ask the drug company if the drug can be used for the patient and see if the drug company will supply it. If the company agrees, the patient’s doctor works with the drug company to ask the FDA to approve the drug for use by this one patient.

The FDA requires the doctor to send information about the patient, why the request is being made, the proposed treatment plan, and a signed informed consent from the patient.The length of time it takes to get single patient access varies. But if it is an emergency, the FDA can complete the paperwork in 24 hours.

Before a patient or group of patients is allowed to have access to an unapproved, new drug outside of a clinical trial two things MUST be in place:

The owner (sometimes referred to as the sponsor, generally a drug company) of the new, unapproved drug must agree to allow the use of their drug outside of the clinical trial, and
The FDA medical officer in charge of the regulatory oversight of that new drug's development must concur before the patient or patients may begin taking the drug.

Many drug companies refuse compassionate use requests. Reasons for refusal may include:

Lack of efficacy - there may be little evidence that the drug may be effective for the specific illness
Safety - the drug may have toxicity problems which aren't public knowledge.
Cost - compassionate use can be expensive, especially large access programs
Production capacity - drugs can be expensive and time-consuming to make, and until approved, capacity to manufacture the drugs may be limited
Priorities - companies may want to use 'left-over' drugs for clinical trials in different illnesses
　
It is important to remember that drug companies are not required to provide their unapproved drug to patients outside of a clinical trial and under no circumstances can a drug company be compelled to do so. The FDA generally supports requests for compassionate use if the patient has exhausted standard treatment options and is ineligible for clinical trials. However, if the FDA is aware of safety issues that may foreshorten a patient's life the FDA may refuse the patient's application. This is a rare occurrence.

In brief an expanded access program is a way of making an investigational drug (unapproved drugs) available to patients without other treatment options, once basic requirements for safety and efficacy have been established, prior to the registration and governmental approval of a new drug by the U.S. Food and Drug Administration (FDA). Patients who participate in expanded access programs have previously exhausted the benefits of approved therapies.

Brand Name Drus Filing Requirements Vs Generic Drugs Filing Requirements

                     (NDA)                                       Vs                        (ANDA)



1. Chemistry                                                 1. Chemistry

2. Manufacturing                                          2.Manufacturing

3.Testing                                                      3.Testing

4.Labeling                                                    4.Labeling

5.Inspections                                                5.Inspections

6.Animal Studies                                         6.Bioequivalence

7.Clinical Studies

8.Bioavailability

Generic drugs are less expensive because it isn’t necessary to repeat:
　
Discovery
Pre-clinical studies
Clinical studies (repeating would be unethical)  

Pharmaceutical Regulatory Agencies and Organizations

This article covers both drugs and device regulatory agencies/organizations across the globe. This article is last updated on 8^th March 2020.

International/Global Regulatory Organizations for Pharmaceuticals
WHO	World Health Organization	The World Health Organization is a specialised agency of the United Nations that is concerned with world public health. It was established on 7 April 1948.
ICH	The International Council for Harmonisation (formerly the International Conference on Harmonisation)	ICH plays major role in bringing together the medicines regulatory authorities and pharmaceutical industry around the world. ICH aims to achieve greater harmonisation worldwide for the development and approval of safe, effective, and high quality medicines in the most resource-efficient manner. It was founded in 1990.
PICS	The Pharmaceutical Inspection Co-operation Scheme	The Pharmaceutical Inspection Co-operation Scheme (PIC/S) was established in 1995 as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970. PIC/S aims at harmonising inspection procedures worldwide by developing common standards in the field of GMP and by providing training opportunities to Inspectors. It also aims at facilitating co-operation and networking between competent authorities, regional and international organisations, thus increasing mutual confidence.
EMA	European Medicines Agency	The European Medicines Agency (EMA) is an agency of the European Union (EU 27) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or European Medicines Evaluation Agency (EMEA).
EDQM	European directorate for the quality of medicines & healthcare	EDQM is a Directorate of the Council of Europe that is responsible for publishing and updatinggranting certificate of suitability,
APIC	Active Pharmaceutical Ingredient Committee	APIC has played and continues to play an important role in improving the regulatory environment for the API manufacturing industry and increasing patient safety.
IPEC	International Pharmaceutical Excipients Council	IPEC Federation is a global organisation that promotes quality and safety in pharmaceutical excipients.

Regulatory Authorities in Europe
Country	Drug Regulatory Authority	Medical Devices Regulatory Authority	Ministry of Health
European Union (EU 27)
Austria	Federal Office for Safety in Health Care (BASG)	Federal Office for Safety in Health Care (BASG)	Federal Ministry of Labour, Social Affairs, Health and Consumer Protection
Belgium	Federal Agency for Medicines and Health Products (FAMHP)	Federal Agency for Medicines and Health Products (FAMHP)	Federal Public Service (FPS) Health, Food Chain Safety and Environment
Bulgaria	Bulgarian Drug Agency (BDA)	Bulgarian Drug Agency (BDA)	Ministry of Health
Croatia	Agency for medicinal products and medical devices of Croatia (HALMED)	Agency for medicinal products and medical devices of Croatia (HALMED)	Ministry of Health
Cyprus	Ministry of Health – Pharmaceutical Services	Ministry of Health – Medical & Public Health Services, Cyprus Medical Devices Competent Authority	Ministry of Health
Czech Republic	State Institute for Drug Control (SUKL)	State Institute for Drug Control (SUKL)	Ministry of Health of the Czech Republic
Denmark	Danish Medicines Agency	Danish Medicines Agency	Ministry of Health
Estonia	Agency of Medicines	Health Board, Medical Devices	Ministry of Social Affairs
Finland	Finnish Medicines Agency (FIMEA)	Finnish Medicines Agency (FIMEA)	Ministry of Social Affairs and Health
France	National Agency for Medicines and Health Products Safety (ANSM)	National Agency for Medicines and Health Products Safety (ANSM)	Ministry for Solidarity and Health
Germany	Federal Institute for Drugs and Medical Devices (BfArM), Paul-Ehrlich-Institut (PEI)	Federal Institute for Drugs and Medical Devices (BfArM)	Federal Ministry of Health
Greece	National Organization for Medicines	National Organization for Medicines	Ministry of Health
Hungary	National Institute of Pharmacy and Nutrition	Department for Medical Devices, National Institute of Pharmacy	Ministry of Human Capacities
Ireland	Health Products Regulatory Authority (HPRA)	Health Products Regulatory Authority (HPRA)	Department of Health
Italy	Italian Medicines Agency (AIFA)	Directorate-General for Medical Devices and Pharmaceutical Service	Ministry of Health
Latvia	State Agency of Medicines	State Agency of Medicines	Ministry of Health of the Republic of Latvia
Lithuania	State Medicines Control Agency	State Health Care Accreditation Agency	Ministry of Health of the Republic of Lithuana
Luxembourg	Ministry of Health	Ministry of Health	Ministry of Health
Malta	Medicines Authority	Malta Competition and Consumer Affairs Authority	Ministry for Health
Netherlands	Medicines Evaluation Board, Farmatec	Farmatec	Ministry of Health, Welfare and Sport
Poland	Office for Registration of Medicinal Products, Medical Devices and Biocidal Products	Office for Registration of Medicinal Products, Medical Devices and Biocidal Products	Ministry of Health
Portugal	Infarmed	Infarmed	Ministry of Health
Romania	The National Agency for Medicines and Medical Devices (NAMMD)	The National Agency for Medicines and Medical Devices (NAMMD)	Ministry of Health
Slovakia	State Institute for Drug Control (SUKL)	State Institute for Drug Control (SUKL)	Ministry of Health of the Slovak Republic
Slovenia	Agency for Medicines and Medical Devices (JAZMP)	Agency for Medicines and Medical Devices (JAZMP)	Ministry of Health
Spain	Spanish Agency of Medicines and Medical Products (AEMPS)	Spanish Agency of Medicines and Medical Products (AEMPS)	Ministry of Health, Consumer Affairs and Social Welfare
Sweden	Medical Products Agency	Medical Products Agency	Ministry of Health and Social Affairs
European Free Trade Association (EFTA)
Iceland	Icelandic Medicines Agency	Icelandic Medicines Agency	Ministry of Health
Liechtenstein	Office of Health	Office of Health	Office of Health
Norway	Norwegian Medicines Agency	Norwegian Medicines Agency	Ministry of Health and Care Services
Switzerland	Swissmedic	Swissmedic	Federal Office of Public Health (FOPH)
Other Countries
United Kingdom	Medicines and Healthcare products Regulatory Agency (MHRA)	Medicines and Healthcare products Regulatory Agency (MHRA)	Department of Health and Social Care
Albania			Ministry of Health
Andorra			Ministry of Health
Belarus	Center for Expertise and Testing in Healthcare	Center for Expertise and Testing in Healthcare	Ministry of Health
Bosnia and Herzegovina	The Agency for Medicinal Product and Medical Devices	The Agency for Medicinal Product and Medical Devices	Federal Ministry of Health
Macedonia	Agency for Medicinal Products and Medical Devices	Agency for Medicinal Products and Medical Devices	Ministry of Health
Moldova	Medicines and Medical Devices Agency	Medicines and Medical Devices Agency	Ministry of Health, Labour and Social Protection
Montenegro	Agency for Medicines and Medical Devices of Montenegro	Agency for Medicines and Medical Devices of Montenegro	Ministry of Health
San Marino			Ministry of Health and Social Security
Serbia	Medicines and Medical Devices Agency of Serbia	Medicines and Medical Devices Agency of Serbia	Ministry of Health
Ukraine	State Service of Ukraine on Medicines and Drug Control	State Service of Ukraine on Medicines and Drug Control	Ministry of Health

Regulatory Authorities in Asia
Country	Drug Regulatory Authority	Medical Devices Regulatory Authority	Ministry of Health
East Asia
China	National Medical Products Administration (NMPA)	National Medical Products Administration (NMPA)	National Health Commission of the People’s Republic of China
Hong Kong	Drug Office - Department of Health	Medical Device Division – Department of Health	Department of Health
Japan	Pharmaceuticals and Medical Devices Agency (PMDA)	Pharmaceuticals and Medical Devices Agency (PMDA)	Ministry of Health Labor and Welfare (MHLW)
Mongolia			Ministry of Health and Sports
North Korea			Ministry of Public Health
South Korea	Ministry of Food and Drug Safety (MFDS)	Ministry of Food and Drug Safety (MFDS)	Ministry of Health and Welfare
Taiwan (ROC)	Food and Drug Administration (FDA)	Food and Drug Administration (FDA)	Ministry of Health and Welfare
South Asia
Afghanistan	General Directorate of Pharmaceutical Affairs, Ministry of Public Health	General Directorate of Pharmaceutical Affairs, Ministry of Public Health	Ministry of Public Health
Bangladesh	Directorate General of Drug Administration (DGDA)	Directorate General of Drug Administration (DGDA)	Ministry of Health and Family Welfare
Bhutan	Drug Regulatory Authority		Ministry of Health
India	Central Drugs Standard Control Organization (CDSCO)	Central Drugs Standard Control Organization (CDSCO)	Ministry of Health and Family Welfare
Maldives	Maldives Food and Drug Authority	Maldives Food and Drug Authority	Ministry of Health
Nepal	Department of Drug Administration (DDA)		Ministry of Health and Population
Pakistan	Drug Regulatory Authority of Pakistan (DRAP)	Drug Regulatory Authority of Pakistan (DRAP)	Ministry of National Health Services, Regulations and Coordination
Sri Lanka	National Medicines Regulatory Authority (NMRA)	National Medicines Regulatory Authority (NMRA)	Ministry of Health
Southeast Asia
Brunei			Ministry of Health
Cambodia	Department of Drugs and Food	Department of Drugs and Food	Ministry of Health
East Timor			Ministry of Health
Indonesia	National Agency of Drug and Food Control	Ministry of Health	Ministry of Health
Laos	Food and Drug Department	Food and Drug Department	Ministry of Health
Malaysia	National Pharmaceutical Regulatory Agency (NPRA)	Medical Device Authority (MDA)	Ministry of Health
Myanmar	Food and Drug Administration	Food and Drug Administration	Ministry of Health and Sports
Philippines	Food and Drug Administration	Food and Drug Administration	Department of Health
Singapore	Health Sciences Authority	Health Sciences Authority	Ministry of Health
Thailand	Food and Drug Administration	Food and Drug Administration	Ministry of Public Health
Vietnam	Drug Administration of Vietnam	Department of Medical Equipment and Health Works (DMEHW)	Ministry of Health
Western Asia/Middle East
Armenia	Scientific Centre of Drug and Medical Technology Expertise	Ministry of Health	Ministry of Health
Azerbaijan	Center for Analytical Examination		Ministry of Health
Bahrain	National Health Regulatory Authority (NHRA)	National Health Regulatory Authority (NHRA)	Ministry of Health
Cyprus	Pharmaceutical Services – Ministry of Health	Department of Medical and Public Health Services – Ministry of Health	Ministry of Health
Egypt	Egyptian Drug Authority	Egyptian Drug Authority	Ministry of Health and Population
Georgia			Ministry of Health, Labour and Social Affairs
Iran	Iran Food and Drug Administration	National Medical Device Directorate	Ministry of Health and Medical Education
Iraq	State Company for Provision of Medicines and Medical Appliances (KIMADIA)	State Company for Provision of Medicines and Medical Appliances (KIMADIA)	Ministry of Health
Israel	Ministry of Health – Pharmaceutical Division	Ministry of Health – Medical Device Division	Ministry of Health
Jordan	Jordan Food and Drug Administration	Jordan Food and Drug Administration	Ministry of Health
Kuwait	Kuwait Drug and Food Control Administration	Kuwait Drug and Food Control Administration	Ministry of Health
Lebanon	Ministry of Public Health	Ministry of Public Health	Ministry of Public Health
Oman	Directorate General of Pharmaceutical Affairs and Drug Control	Directorate General of Pharmaceutical Affairs and Drug Control	Ministry of Health
Palestine	General Directorate of Pharmacy	General Directorate of Pharmacy	Ministry of Health
Qatar	Pharmacy and Drug Control		Ministry of Public Health
Saudi Arabia	Saudi Food and Drug Authority	Saudi Food and Drug Authority	Ministry of Health
Syria	Directorate of Drug Control		Ministry of Health
Turkey	Turkish Medicines and Medical Devices Agency	Turkish Medicines and Medical Devices Agency	Ministry of Health
United Arab Emirates			Ministry of Health and Prevention
Yemen	Supreme Board for Medicine and Medical Appliances	Supreme Board for Medicine and Medical Appliances	Ministry of Public Health
North/Central Asia
Kazakhstan	National Center for Expertise of Medicines and Medical Devices	National Center for Expertise of Medicines and Medical Devices	Ministry of Healthcare
Kyrgyzstan	State Department of Medicine Provision and Medical Equipment	State Department of Medicine Provision and Medical Equipment	Ministry of Health
Russia	Federal Service for Surveillance in Healthcare (Roszdravnadzor)	Federal Service for Surveillance in Healthcare (Roszdravnadzor)	Ministry of Health
Tajikistan			Ministry of Health
Turkmenistan			Ministry of Health and Medical Industry
Uzbekistan	National Information and Analytical Center on Drugs Control		Ministry of Health
Oceania
Australia	Therapeutic Goods Administration (TGA)	Therapeutic Goods Administration (TGA)	Department of Health
New Zealand	Medicines and Medical Devices Safety Authority (MEDSAFE)	Medicines and Medical Devices Safety Authority (MEDSAFE)	Ministry of Health
Papua New Guinea	Pharmaceutical Services Standards Branch - National Department of Health	Pharmaceutical Services Standards Branch - National Department of Health	National Department of Health

Regulatory Authorities in Americas
Country	Drug Regulatory Authority	Medical Devices Regulatory Authority	Ministry of Health
Argentina	National Administration of Drugs,Foods and Medical Devices (ANMAT)	National Administration of Drugs,Foods and Medical Devices (ANMAT)
Brazil	Agencia Nacional de Vigilancia Sanitaria (ANVISA)	Agencia Nacional de Vigilancia Sanitaria (ANVISA)	Ministry of Health
Canada	Health Canada	Health Canada
Latin America	Panamerican health organization	Panamerican health organization
US	United States Food & Drug Administration (USFDA)	USFDA

Regulatory Authorities in Africa
Country	Drug Regulatory Authority	Medical Devices Regulatory Authority	Ministry of Health
South Africa	South African Health Products Regulatory Authority (SAHPRA)	South African Health Products Regulatory Authority  (SAHPRA)

You may also like following posts

Pharmaceutical Glossary (Terminologies and Definitions)

https://pharmatreasures.blogspot.com/2013/11/terminology-and-definitions-in.html?spref=bl

Common Abbreviations/Acronyms in Pharmaceuticals

https://pharmatreasures.blogspot.com/2013/12/common-abbreviations-used-in.html?spref=bl