Quality Control Status of Inhaled Drugs in Pharmaceuticals Sector of Bangladesh: Is US-FDA guidelines working for Bangladesh? Is there any guideline set by Directorate General of Drug Administration (DGDA) of Bangladesh?

Inhaled Medication:
There are several asthma medications available in Bangladesh in inhaled form. An inhaler or puffer is a medical device and inhalation dosage forms are intended to deliver drugs to the lungs. It is mainly used in the treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). The lungs have a large surface area and a rich blood supply to the alveolar epithelium both of which favor rapid absorption. Examples of drugs administered by inhalation include corticosteroids (e.g., fluticasone, Prednisone, Prednisolone), adrenocorticoid steroids (e.g., beclomethasone), bronchodilators (e.g., Salbutamol/ albuterol, isoproterenol, metaproterenol), and antiallergics (e.g.., cromolyn).

Inhaled Drug formulation:
Inhalation formulations are generally solutions, suspensions, and powders. These formulations are administered via an aerosol or a dry powder inhaler. Aerosols are devices where liquid or suspension droplets are the internal phase and a gas is the external phase. Commercial aerosols are typically metered dose inhalers (MDI) that deliver a fixed dose in a spray with each actuation of the device. For compounded inhalation solutions, atomizers, nebulizers, and vaporizers are the aerosol devices.
Inhaler Types:
Pressurized Metered-dose inhalers (pMDI)
pMDI — The most common type of inhaler is the pressurized metered-dose inhaler (MDI). In MDIs, medication is most commonly stored in solution in a pressurized canister that contains a propellant, although it may also be a suspension. The MDI canister is attached to a plastic, hand-operated actuator. On activation, the metered-dose inhaler releases a fixed dose of medication in aerosol form. The correct procedure for using an MDI is to first fully exhale, place the mouth-piece of the device into the mouth, and having just started to inhale at a moderate rate, depress the canister to release the medicine. The aerosolized medication is drawn into the lungs by continuing to inhale deeply before holding the breath for 10 seconds to allow the aerosol to settle onto the walls of the bronchial and other airways of the lung.
Dry powder inhalers (DPI)
DPI — Dry powder inhalers release a metered or device-measured dose of powdered medication that is inhaled through a DPI device. Commercially available dry powder inhalers contain their dry powders in manufactured cartridges or disks. When the patient administers a dose, the device is first activated by some mechanical motion and the dry powder becomes ready for inspiration. Then the patient inhales through the device mouthpiece and the powder is drawn into the pulmonary tract along with the inspired air. These devices have overcome a major problem of inhalation therapy, synchronizing deep inspiration with the administration of the drug. Some of these devices are Diskhaler®, Turbuhaler®, Diskus®, and Rotahaler®.
Nebulizers — supply the medication as an aerosol created from an aqueous formulation. A nebulizer contains an atomizing unit within a chamber. When the rubber bulb is depressed, the medication solutions is drawn up a dip tube and aerosolized by the passing air stream. Baffles or beads may also be present in the chamber. The fine droplets exit the nebulizer. The larger droplets collect on the chamber and fall back into the reservoir where they can be used again.

Inhaled Drug Manufacturer in Bangladesh
According to the Directorate General of Drug Administration (DGDA) of Bangladesh currently there are 267 Allopathic drug manufacturing companies in Bangladesh. Among them some top pharmaceuticals manufacturing companies like Beximco, Square, Incepta, ACME, ACI, Healthcare, Aristopharma and GSK Pharmaceuticals are manufacturing Inhaled drugs for Bangladesh market and few of them for export market.

Inhaler User in Bangladesh
In accordance with National Asthma Prevalence Study (NAPS) about seven million people are suffering from current asthma in Bangladesh. Another separate report on 16th July, 2011 by Mr. Anisur Rahman Khan about 10 million people now suffering from Bronchial Asthma in Bangladesh, up from seven million in 2002. In Dhaka city alone, there has been a 15 per cent increase in the number of patients seeking treatment for asthma in various city hospitals. According to the Directorate general of Health Services (DGHS) Bangladesh report in 2009 causes of mortality only in the National Institute of Diseases of Chest and Hospital deaths followed by chronic obstructive pulmonary disease was 16.77%. According to the http://www.worldlifeexpectancy.com in Bangladesh death rate followed by Asthma is 8.8% per 100,000 persons and in world ranking Bangladesh is in position 64 numbers among 192 countries. It is estimated that around 300 million people in the world currently have asthma and it accounts for about 1 in every 250 deaths worldwide.
Parvin et al. (2011), stated that a study in Bangladesh shows that only 17% asthma patients could demonstrate the technique of inhaler use properly. Another study shows that 69.6% of bronchial asthma patients are lacking the knowledge of correct use of inhaler.

US-FDA Guidelines for Pharmaceutical Quality Assessment of Inhaled Drug Products
To protect the huge numbers of death tolls associated by asthma and Chronic Obstructive Pulmonary Disease (COPD) and to deliver quality medicine for these patient groups US-FDA set some guidelines to ensure the quality of inhaled drug products. These guidelines are applicable for Metered Dose Inhaler (MDI), Dry Powder Inhaler (DPI), Nasal Spray (NSP) and Nebulizer testing.

Particle Size Analysis by LASER Diffraction
Particle Size Distribution is a very much important parameter to be tested before drug product release. A correct particle size distribution ensures the bioavailability of the active drug on the target site of action. An unapproved particle size distribution may lead to waste of drug doses and decreased efficacy of the dose. For example, a very fine particle/droplet distribution of Nasal Spray (<10 micron) will deposit more spray droplets in the lungs and gastrointestinal tract than the nasal passageway which is the target site of action. To ensure maximum deposition of the spray droplets in the nasal passageway the particle size should be more than 10 micron. For MDI and DPI particle size distribution should be in the range of 1-5 micron. Therefore, particle size distribution analysis is an obligatory test before product release.
FDA recommends using LASER DIFFRACTION technology for particle sizing of various pharmaceutical products.

Aerodynamic Particle Size Distribution
The devices used for inhaled and nasal drug delivery are collectively referred as Orally Inhaled and Nasal Drug Products, OINDPs.
It is widely recognized that Aerodynamic Particle Size Distribution (APSD) is a Critical Quality Attribute in the in vitro characterization of OINDPs. To be therapeutically effective the particle size of OINDPs should be in a particular size range. For example, MDI and DPI particle size should be in the range of 1-5 micron. Particles greater than 5 micron will generally go to the gastrointestinal tract and particles smaller than 1 micron will come out with exhalation. Particles between 1-5 micron have greater chance to be deposited in the lungs which is the target site of deposition.
Cascade Impaction is the sampling procedure for APSD analysis. Cascade Impactor collect particles of different sizes from an inhaler/spray/nebulizer. For Example, the particles of different sizes may range in 0.4-0.7 micron, 0.7-1.1 micron and 1.1-2.1 micron and so on. There are different cups in the cascade Impactor to collect particles of different size ranges. The collected particles of different size ranges in different cups are then sent to analyze the Active Pharmaceutical Ingredient (API) by drug assay procedure.
Thus, which size of particles carry more drugs can be identified. In more simple word, APSD is like distributing the drug particles into different cups according to their size. Then the drug particles of each cup are chemically measured to identify the delivered drug content.

Spray Pattern and Plume Geometry
Have you ever wondered what shape the spray or aerosol you have really produces from your MDI/DPI or NSP? For a variety of reasons, these drug delivery methods need characterization. Following is a piece of information from CMC (chemistry, manufacturing, and controls) guideline on the importance of Spray Pattern and Plume Geometry analysis.
Characterization of spray pattern and plume geometry is important for evaluating the performance of the pump. Various factors can affect the spray pattern and plume geometry, including the size and shape of the nozzle, the design of the pump, the size of the metering chamber, and the characteristics of the formulation.
Spray pattern testing should be performed on a routine basis as a quality control for release of the drug product.

Dose Content Uniformity (Within Batch)
Dose content uniformity (DCU) is the test which ensures the uniform distribution of active drugs in the MDIs/DPIs/NSPs/Nebulizers of a batch. The same test for Nasal Spray (NSP) is called Spray Content Uniformity (SCU) which is also performed within a batch. The test checks the active drug content of a number of MDIs/DPIs/NSPs/Nebulizers from a batch. For Example, 10 MDI units are randomly collected from a lot.
Then the 10 MDIs are actuated in 10 different collection tubes to collect the doses. These 10 collection tubes containing the actuated doses are then assayed to measure the active drug content. The result of this assay helps to identify if there is any unapproved variation in active drug contents in the tested MDI products. It also helps to compare the drug content uniformity among batch-to-batch.

Dose Content Uniformity (Within Container)
Dose content uniformity through container life is the test which ensures the uniform dose distribution of active drug(s) throughout the life of an MDI/DPI/NSP canister/bottle/container. The same test for Nasal Spray (NSP) is called Single Actuation Content (SAC) through container life. The test checks the active drug(s) content of one (sometimes two or three) MDI/DPI/NSP container(s). For Example, 1 MDI unit is randomly collected from a lot. Then the MDI is actuated 10 times (3 in the beginning + 4 in the middle + 3 at the end) in 10 different collection tubes to collect the doses. These 10 collection tubes containing the actuated doses are then assayed to measure the active drug content. The result of this assay helps to identify if there is any unapproved variation in active drug contents in the tested MDI product throughout its life.
Dose Weight (Valve Delivery)
Dose weight also known as shot weight or valve delivery, is a measure of the weight of the formulation delivered through the valve of an inhaled drug device. It is measured by the difference of weight per actuation or per dose. This test is directly related to the metering ability of the valve, and it evaluates valve-to-valve reproducibility of the drug product.

When you spray any MDI/DPI/NSP for the first time it may not spray properly. Then you may need to waste some medicine by spraying 2 or 3 times to get a full spray. By spraying 2 or 3 times you blow out the air from the spraying valve and then the medicine comes out in full spray. Priming/Re-priming is the actuation numbers required before getting a correct spray of medication. The correct spray means the recommended dose or label claimed dose of an MDI, NSP or sprayed medication. A study should be conducted to find out how many spray is required (priming actuations) before getting a correct spray for the first time for a user. The user may take the medicine again after some time, for example, after 8 hours. The waste sprays required before getting a full spray after 8 hours will be the re-priming sprays. In simple words, priming/re-priming is the wasting of sprays to get a full spray for the first time and in subsecuent actuation with a time lapse.
Containers should be stored in various orientations prior to the initiation of the study in order to determine the effect of orientations. The length of storage prior to conducting the study should be indicated and justified. Priming instructions should be provided to the health care professional and the consumer.

Tail off testing is performed to determine the rate at which an MDI transitions from delivering complete doses to no delivery at all. It is the test of the container’s drug content after actuating/finishing the label claimed doses. The ideal is a rapid transition from complete doses to no delivery so that the patient is receiving partial doses for as few actuations as possible. For example, test a container for its drug content after actuating 200 label claimed doses of an MDI. It may also be measured by priming/repriming or Dose Weight (Valve Delivery). Measurement of tail off by Dose Weight does not assure that the drug substance is being delivered because most of the weight of an actuation is due to the propellant.

Leak Rate
Leaking of propellant(s) is measured by weight change of MDIs as a function of time stored at controlled conditions. Weight loss is determined by measuring the initial weights of canisters that are placed on condition and then reweighed at subsequent time points.

Spray Force Tester
Sometimes patients abort the inhalation process due to the cold impaction of MDI propellants on patient’s throat. Similar reaction can be generated by NSP.
Recent work by the FDA highlights the application of spray impaction force for in vitro equivalence studies, and raises the possibility of using maximum force measurements at different distances from the mouthpiece for quality control purposes.

Is there any guideline for Inhaled Drugs in Bangladesh?
Inhalers are used in chronic condition of patients and in every actuation micro gram amount of drugs are delivered. If inhaled drugs manufacturers are unable to ensure the quality of inhaled drugs as like US-FDA guidelines patients with chronic asthma and Chronic Obstructive Pulmonary Disease (COPD) may face death. For the developed countries there are strict guidelines for every medicine manufacturing and quality control. Albeit, we are not citizen of developed countries but we are the same human being as like Europe and USA. We believe top pharmaceuticals manufacturing companies in Bangladesh manufacturing and controlling the quality of inhaled drugs as like US-FDA guidelines. Since, inhaled drugs may use for medication of 10 million people of Bangladesh in this circumstances government authority like DGDA and pharmaceuticals manufacturer should have positive thinking to set up and follow the guidelines for inhaled drugs.

Muhammad Zahidul Hoque
Chairman & CEO
BIO-XIN (pvt) Ltd
Email: zahid.bioxin@gmail.com
Cell: +88-01922997784

FDA Draft Guidance for Industry Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation
Parvin et al., (2011), Knowledge about inhaler use among the chronic asthma patients in selected hospitals. Bangladesh Med Res Counc Bull 2011; 37: 47-50
The Pharmaceutics and Compounding Laboratory, UNC Eshelman School of Pharmacy, USA, http://pharmlabs.unc.edu/index.htm