The Pharmaceutical Industry Manufacturing Processes

The Pharmaceutical Industry Takes the active ingredients of drugs and converts them into a form that can easily be given to a patient. Involves mixing the active ingredient/s with various other ingredients with appropriate chemical properties, then either compressing the mixture into tablet, filling a gelatin capsule with it or dissolving it in an appropriate solvent.

Advantages of Industrial Production Low prime cost (including innovations) Large scale production Unified package (good for transportation) Quality control processes (standard technical documentation)

Standard Technical Documentation Necessary to provide us with safe, effective and qualitative medicines Pharmacopoeia Technology and technical regulations State standards Producer Pharmacopoeia articles SOPs CGMPs

Basis of most technological processes – dosage form of drug Solid dosage forms (tablets, capsules, powders, granules, dragee, …) Liquid dosage forms (solutions, suspension, emulsion) Soft dosage forms (ointments, liniments, capsules, patches, gels…) Gaseous dosage forms (gases, aerosols)

Definitions Medicine is defined in the Medicines Act 1981 as “any substance or article other than a medical device that is manufactured, imported, sold or supplied wholly or principally for administering to one or more human beings for a therapeutic purpose Where a therapeutic purpose is defined as treating, preventing, or diagnosing disease.”

Tablet Solid dosage form that is prepared by compressing or molding of the drug into various sizes and shapes. The most common means of administering a medicine. Tablets are compressed powder, formulated so as not to break up or chip before being taken, but to disintegrate in the digestive tract and release the drug in a consistent and predictable manner.

Tablet Dissolution is the rate-limiting step in the delivery of drug from a tablet to the systemic circulation. This requirement, and the requirement that the drugs be of suitable size to be taken, means that there is more involved in the tablet making than simply taking a powder and compressing it.

Advantages Production aspect Large scale production at lowest cost Easiest and cheapest to package and ship High stability User aspect (doctor, pharmacist, patient) Easy handling Lightest and most compact Greatest dose precision & least content variability

Disadvantages Some drugs resist compression into dense compacts Drugs with poor wetting, slow dissolution, intermediate to large dosages may be difficult or impossible to formulate and manufacture as a tablet that provide adequate or full drug bioavailability Bitter taste drugs, drugs with an objectionable odor, or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating

Tablets for Oral Administration Film coated tablets Enteric coated tablets Effervescent tablets Sublingual tablets Buccal tablets Troches Chewable tablets Controlled release tablets - slow release tablets (SR) and modified release tablets (MR)

Tableting Step 1: Dispensing Sufficient active ingredient to make up a batch is weighed out, and at the same time the first of the excipients to be used is added to the mixture. The excipients used as this stage are fillers (to dilute the active) and binders: either lactose or polyvinyl pyrrolidine (both of which act as both fillers and binders).

.....Step 1 The quantity of excipient required in any tablet can vary considerably depending upon the active ingredient, the tablet size required and the dose. For example: aspirin tablets are only approximately 10% excipient, while other tablets are more than 99% excipient.

Step 2: Granulation The stage in which the tablet ingredients are thoroughly mixed, and prepared for compressing. Two different methods are used, with the choice of method based on particle size and shape. Dry granulation Wet granulation

Dry Granulation The simpler of the two methods, and is suitable for tablets where the particle size of both the active and the excipients are the same. The active ingredient and the excipients are sieved through a fine mesh and thoroughly mixed. If the particle size differs, desegregation can occur in the tablet hopper during the compression stage leading to non-uniform dispersion of the active in tablets.

Wet Granulation More complicated, but is more commonly used. It is necessary for tablets in which the active ingredient and excipients have different particle sizes. It also helps tablets with very spherical particles to bind together, by making them more lumpy in shape.

....Wet Granulation The dry mixed ingredients from the dispensing stage are mixed with liquid – usually a paste made of maize starch and water, sometimes water or alcohol. These are mixed to form a dough, cut into very small pieces, and are dried below 60OC either in a hot air oven or a fluid bed drier until they are < 2% moisture. The dried pieces are milled into very small granules and blended with a salt of a fatty acid or talc. Salt of a fatty acid – magnesium stearate Talc – a mixture of magnesium silicates

....Wet Granulation This powder coats the granules of the other ingredients, and acts a lubricant to reduce friction during the compression and ejection of the tablets. But, lubricants also reduce the rate at which tablets disintegrate and dissolve in the digestive tract.

The classification of manufacturing methods wet granulation: suitable for drugs that are stable to moisture and heat dry granulation: suitable for drugs that are sensitive to moisture and heat powder compression : suitable for drugs that are sensitive to moisture and heat, fill material possessing, good flowability and compressibility granulation direct compression crystal compression：suitable for drugs with proper crystal form and good flowability

Step 3: Compression Tablets are compressed on machines that can usually produce 16, 32, or 64 tablets per rotation. The weight and strength of the tablet is controlled by adjustment of the volume of the die into which the powder for each individual tablet is fed immediately prior to compression. The main components of single-punch tablet presses: die; lower punch; upper punch

The main components of single-punch tablet presses Core components: die lower punch upper punch

....compression The compression machine is loaded with dies that either simply compress the powder into a tablet of suitable size and shape, or that also emboss them with various identification marks or put a groove in them so that they can be broken in half. Tablet production may be finished at this stage or if required, they can proceed on to being coated.

Classes of Tablet Presses a. single-punch presses b. multi-station rotary presses

The compression cycle of a rotary tablet press

Compressed Tablets Contains: Medicinal agent Diluents or filler Binders or adhesives Disintergrants Lubricants Miscellaneous adjuncts Colorants and flavorants

Diluents Diluents increase the volume to a formulation to prepare tablets of the desired size. Widely used fillers are lactose, dextrin, microcrystalline cellulose starch, pre-gelatinized starch, powdered sucrose, and calcium phosphate.

Binders Binders promote the adhesion of particles of the formulation. Such adhesion enables preparation of granules and maintains the integrity of the final tablet. Commonly used binding agents include: water, ethanol, starch, gelatin and sugars (sucrose, glucose, dextrose, and lactose).

Disintegrants The breakup of the tablets to smaller particles is important for dissolution of the drug and subsequent bioavailability. Disintegrators promote such breakup. To rupture or breakup of tablets, disintegrating agents must swell or expand on exposure to aqueous solution. Thus, the most effective disintegrating agents in most tablet systems are those with the highest water uptake property. In general, the more hydrophilic, the better disintegrating agents are therefore highly hydrophilic.

Lubricants A substance capable of reducing or preventing friction, heat, and wear when introduced as a film between solid surfaces. It works by coating on the surface of particles, and thus preventing adhesion of the tablet material to the dies and punches. Lubricants play more than one role in the preparation of tablets. Commonly used lubricants include: talc, magnesium stearat, calcium stearate ,stearic acid, hydrogenated vegetable oils and PEG.

Step 4: Tablet Coating Tablets may be coated to: improve the stability Improve appearance Mask an unpleasant taste Protect the tablet from the acid in the stomach For easy identification Improves stability by protecting the tablet from exposure to light, moisture, or air

Tablet Coating The general methods involved in coating tablets are as follows 1) sugarcoating tablets 2) film-coating tablets 3) fluid-bed or air suspension coating 4) compression coating 5) Enteric coating Enteric coating – one that doesn’t dissolve in the acid conditions of the stomach. - produced from Cellulose Acetate Phthalate (CAP), dissolves in more alkaline conditions of the small intestine

....Tablet Coating Sugar coating – most common type of coating used; but requires application of up to 27 coats of different sugar, sealing and polishing coats. Film coating is nowadays used. The polymer used (hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose or carboxymethylcellulose sodium – cellulose polymers with different functional groups in place of some or all of the – OH groups) is simply mixed with water or another appropriate solvent.

....film coating This solution is sprayed onto the tablets as they are turned in a large rotating bowl, the solvent evaporates off, and a layer of film remains on each tablet. Film coatings have the advantage that they can be applied to embossed tablets without the embossing being filled up with coating solution.

Quality Standards and Compendial Requirements The apparent physical features of compressed tablets: 1) shape: round, oblong, unique 2) thickness: thick or thin 3) diameter: large or small 4) flat or convex 5) unscored or scored in halves, thirds and quadrants 6) engraved or imprinted with an identifying symbol and/or code number 7) coated or uncoated 8)colored or uncolored 9) number of layers.

Other physical specifications and quality tablet weight weight variation content uniformity tablet thickness tablet hardness tablet disintegration drug dissolution in-process controls verification after the production

Tablet Hardness 1)The greater the pressure applied, the harder the tablets. 2) The hardness required by different tablets a) lozenges and buccal tablets: hard (dissolve slowly) b) the tablets for immediate drug release: soft 3) Measurement a) special dedicated hardness testers b) multifunctional equipment

Friability 1) It is used to determine a tablet’s durability 2) Method: allowing the tablets to roll and fall within the rotating apparatus (friabilator); determine the loss in weight; 3) requirement: weight loss ≤1%

Tablet Dissolution 1) The importance of in vitro dissolution test a) to guide the formulation and product development process toward product optimization b) to monitor the performance of manufacturing process c) to assure bioequivalence from batch to batch d) as a requirement for regulatory approval for product marketing for products registered with the FDA and regulatory agencies of other countries.

2) The goal of in vitro dissolution is to provide a reasonable prediction of the product’s in vivo bioavailability. Basis: The combinations of a drug’s solubility and its intestinal permeability are supposed as a basis for predicting the likelihood of achieving a successful in vivo – in vitro correlation (IVIVC).

3) The formulation and manufacturing factors affecting the dissolution of a tablet a) the particle size of the drug substance b) the solubility and hygroscopicity of the formulation c) the type and concentration of the disintegrant, binder, and lubricant used d) the manufacturing method, particularly, the compactness of the granulation and the compression force e) the in-process variables

Some Special Areas of Drug Production drugs Galenical (extraction of medicinal plants: tinctures, extracts …) biotech pharmaceuticals children's medicines ophthalmic formulations geriatric medicines

Drugs: Galenicals The process of extraction refers to the mass-transfer processes and flows through the diffusion laws The main factors are: nature and characteristics of medicinal herbs Properties of the extracting agent (water, ethanol, ethyl ether, chloroform, acetone, liquefied gases )

Main stages of production Raw material preparation Extraction process Purification (settling, filtration, centrifugation) Concentration or drying Filling and packing

Galenicals

Galenicals: Quality Control Organoleptic characteristics (transparency, chromaticity, taste, flavor) Ethanol content and dencity (in tinctures) Dry residue Heavy metals