DEVELOPING A GENERIC DRUG PRODUCT

by:John C Carter, Carter Pharmaceutical Consulting, Inc.
© 2003 -2006. All Rights Reserved

Carter Pharmaceutical Consulting, Inc.Having worked in the Pharmaceutical Industry for the past 23 years, 10 of them on the “Generics” side of the business, I have come to intimately learn how product development is handled for both brand name and generic products. Certainly there are some obvious differences. However, there are also many similarities. After all, whether it’s a generic product or a brand name product, the physical development of any product will require a formulator to:

  • Choose from the same types of available excipients
  • Choose from the same types of available processes
  • Utilize similar types of equipment, in similar types of facilities, meeting similar regulations

Some people still truly believe that generic products are inferior top brand name products. However, the facts are:

  • Generic products must meet the same quality standards as brand name products
  • The efficacy of generic products vs. the designated reference product must be proven through the use of a bioequivalency study
  • The facilities and procedures used to manufacture generic products must meet the same cGMP requirements as brand name products

Admittedly, there can be both good product development and poor product development practices in either brand name or generic pharmaceutical companies. Fortunately stricter regulatory and process validation requirements have helped to weed out poorly developed products making the proper development of robust formulations more essential than ever.

Based on my experiences, the following slides represent some suggested steps needed to successfully develop generic products.   

Although this information primarily concerns solid oral dosage forms, many of the general principles discussed here would be applicable to generic semi-solid or liquid products as well.

Prior to Development:    

A product for development must be selected. In order to properly select a product, input is needed from a variety of disciplines including:

  • R&D
  • Regulatory Affairs
  • Legal
  • Marketing & Sales
  • Finance, etc.    

Once selected, details of the selected product should be recorded into some kind of document to include information such as:

  • Innovator Product Description and Dosage Form
  • Innovator Product Packaging Description
  • Innovator Product Sales
  • Generic Product Description and Dosage Form
  • Generic Product Packaging Description
  • Generic Sales Forecasts
  • Intended Manufacturing Site
  • Intended Production Batch Size
  • Any other relevant information    

Based on patent expiry, product exclusivity, forecasts, availability of the active ingredient etc., the project needs to be scheduled and its’ progress tracked and managed with the goal of being the first generic drug manufacturer (for that particular product) on the market.

Pre-formulation:    

Prior to preparing actual trial formulations, “pre-formulation” work must be performed to obtain as much information about the reference product and drug substance as possible.

Common pre-formulation activities include the following:

  • Review of the product selection document
  • Review of any pertinent patent information
  • Obtain samples of reference product and packaging
  • Evaluate physical characteristics of the reference product
  • .Determine reference drug release characteristics through “in-vitro” dissolution profiling.
  • Obtain and review all available public information about the innovator or “reference” product i.e. PDR, CPS, Merck Index, product labels and inserts, published literature in pharmaceutical and medical journals, etc.
  • Characterize drug substance to determine drug form (i.e. crystalline, powder, amorphous), drug solubility, polymorphism, particle size, bulk density, flow characteristics, chemistry (i.e. pKa, functional groups), drug absorption characteristics (pharmacokinetics), incompatibilities, sensitivities (light, heat, moisture), etc.
  • Identify a discriminating dissolution procedure with relevant in-vitro/in-vivo correlations    

Following these “pre-formulation” activities, decisions can be made as to the type of formulation and process to be considered for development.     (Dosage form and dosage strength are determined by the reference product itself, and by the requirements detailed in the product selection document.)  

There are three general processes used to produce tablets and capsules, as follows:    

Direct Mix:

This process involves simply blending the drug substance with excipients and compressing the mixture into tablets or filling it into capsule shells.       

Dry Granulation:

This process involves processing the drug substance with excipients using a “slugging” or “compaction” technique followed by “granulation sizing” and final blending with additional excipients prior to tablet compression, or capsule shell filling.   

Wet Granulation:

This process involves processing the drug substance with excipients and a solvent in which a binder may be dissolved to produce a granulation. The granulation is subsequently dried, sized and blended with additional excipients prior to tablet compression or capsule shell filling.

Whenever possible or practical, a direct mixing process is initially considered since this process usually offers the simplest and most economical means to produce a solid pharmaceutical dosage form. However, the product dosage, physical drug characteristics, and even characteristics of the reference product itself, will ultimately determine what type of process is feasible.     

A tablet or capsule dosage form will generally contain the following components:

  • Active Ingredient- Drug substance
  • Binder- Holds filler and drug particles together in agglomerates to form granules or tablets or capsule slugs, etc.
  • Solvent- Used in “wet granulations” as the granulating medium
  • Fillers/Diluents- Used to provide bulk or weight to tablets and capsules to make tablets or capsules of a practical size for administration
  • Disintegrating Agent- Used to cause granules and/or tablets and/or capsule contents to break apart to enhance the availability of drug substance for dissolution and absorption
  • Glidant- Used to reduce inter-particulate friction thereby improving flow characteristics
  • Anti-adherent- Similar role as lubricant, but more specialized for effectiveness at preventing adhesion to equipment surfaces. (Should be used in combination with a lubricant.)
  • Lubricant- Used to prevent sticking of powders to equipment used to compress tablets or fill capsule shells (i.e. tablet punches and dies, encapsulating dosators or tamping pins).

 

Others:

  • Dyes-Impart a colour to the tablet
  • Sweetening Agents & Flavours- Used in chewable tablets.
  • Wetting Agents- Used to enhance drug substance ‘wetting’ and solubility.
  • Acidifying Agents, Buffers, Stabilizers, Etc.- Excipients added to provide a more stable environment for the drug substance involved.
  • Film Coating Preparations- If a tablet is to be film-coated, the components of the material used for coating will include a polymeric film-former, a plasticizer, and may or may not include, an opacifying agent, a dispersing agent, one or more dyes, etc.

 

It is impossible to list every conceivable example or potential use for the large number of excipients available to fulfill the various roles as components of tablet and capsule formulations.

Therefore, only some of the most common excipients and their suggested use levels are listed as follows:

Binders:

  • Polyvinylpyrrolidone (PVP)-0.5-5%
  • Pregelatinized starch - 5-10% (wet), 5-20% (direct)
  • Starch paste- 5-25% w/w        
  • Microcrystalline cellulose - 5-25% (wet), 5-25% (direct)
  • Sucrose- 50-70% solution
  • Hydroxypropyl cellulose- 4-6%
  • Ethylcellulose- 5% solution
  • Methylcellulose- 1-5% solution (depending on viscosity grade)
  • Acacia- 1-5%    

 

Solvents:

  • Purified water
  • Ethanol
  • Purified water/ethanol
  • Other organic solvents (i.e. Methylene Chloride)

 

Fillers/Diluents:

  • Microcrystalline cellulose
  • Lactose
  • Starch/pregelatinized starch
  • Dicalcium phosphate
  • Calcium carbonate
  • Compressible sugars
  • Mannitol
  • Sorbitol

 

Disintegrating Agents:

  • Sodium starch glycolate- 4-8%
  • Croscarmellose sodium- 3-6%
  • Pregelatinized starch- 5-10%
  • Starch- 5-10%
  • Microcrystalline cellulose- 5-15%
  • Cross-linked polyvinylpyrrolidone- 2-5%
  • Alginic Acid- 5-10%

 

Glidants/Lubricants/Antiadherents:

  • Fumed silicon dioxide (glidant)-0.1-0.5% (anti-adherent)-1-2%
  • Talc (anti-adherent)- 1-4%
  • Magnesium stearate- 0.25-1.5%
  • Stearic acid- 0.5-3%
  • Hydrogenated vegetable oils- 2-5%
  • Sodium lauryl sulfate- 1-3%
  • Mineral oil- 1-3%

 

Others:

  • Dyes- Usually aluminum lakes: water soluble dyes precipitated with the hydrous oxide of aluminum.
  • Sweetening Agents & Flavours- Compressible sugars/alcohols & various flavouring agents.
  • Wetting Agents- Sodium lauryl sulfate- 0.1-2%,
  • Polysorbate 80- 0.1-3% 
  • Acidifying Agents, Buffers, Stabilizers, etc.-
  • Citric acid- 0.3-2%
  • Sodium citrate- 0.3-2%(dihydrate)
  • Sodium phosphate monobasic

 

Considerations for Selecting Excipients in a Formulation:

  • Composition of Reference Product (if available)- PDR, CPS or product labels will often list qualitative composition of formulations.
  • Requirement for Specific Excipient- Formulations should start out simple, with additional, specialized excipients being incorporated as needed through experimental trials.
  • Drug/Excipient Incompatibilities- Drug characterization and pre-formulation studies may exclude specific excipients due to potential incompatibility or stability issues.
  • Excipient Characteristics/Affect on Drug Substance Release- Depending on the drug substance, certain excipients may be selected due to their affect at enhancing or retarding the release of the drug substance to produce the desired “in-vitro” dissolution release profile.
  • Formulation Process- Certain excipients are specialized for direct mixing processes whereas others are more suitable for wet granulation processes.
  • Availability- Excipients most readily available are usually selected over excipients that may be equally adequate, but not readily available.
  • Experience- Formulators usually select excipients with which they have the most experience, even though there may be equivalent excipients to perform the same function.
  • Cost- With two functionally equivalent, equally available excipients, the cheaper of the two may be selected.

 

Formulation Development:    

Once pre-formulation work and a development strategy are completed, a series of small-scale trials are prepared. These trials involve processing the drug substance with excipients using the selected process to produce a dosage form with the desired strength and appearance dictated in the product selection document. The dosage form is then physically and chemically evaluated to determine its acceptability relative to the reference product.

The following represents the common types of testing performed on tablet and capsule formulations under development:    

Blends-    

Physical Testing: Bulk and tapped density, particle size distribution, flow index, angle of repose, moisture and/or L.O.D.    

Chemical Testing: Blend uniformity         

 

Tablets-      

Physical Testing: Appearance, average weight and weight variation, hardness, thickness, friability, disintegration time    

Chemical Testing: Dissolution profiles vs. reference product, assay, content uniformity, chemical identification, impurities and related substances, ICH stability     

 

Capsules-    

Physical Testing: Appearance, average weight and weight variation, disintegration time           

Chemical Testing: Dissolution profiles vs. reference product, assay, content uniformity, chemical identification, impurities and related substance, ICH Stability

Development trials continue until a formulation with a matching dissolution profile, relative to the reference product, is obtained in one or more dissolution media.    

This formulation should then be scaled-up to a slightly larger size and the resulting dosage form packaged, and placed on accelerated stability stations for monitoring. In the meantime, additional trials should be prepared to optimize various formulation and process parameters.

These optimization trials are very important and serve to:      

  • Provide experience with the new formulation and process.
  • Determine limitations by challenging various process parameters
  • Provide additional data necessary for setting meaningful specifications
  • Identify significant formulation or processing issues that can be addressed before the product formulation and process is “locked” (i.e. prior to bioequivalency testing)    

 

If the product retains acceptable physical and chemical characteristics, it is further scaled-up under GMP conditions to serve as the “test batch” for “in-vivo bioequivalency testing” vs. the reference product. If the product proves to be “non-bioequivalent” to the reference product, reformulation is required, assuming that the continued development of this product remains economically viable due to this delay.     

If the product proves to be “bioequivalent” to the reference product, a submission package is assembled and submitted to the respective Government Regulatory Agency for review and eventual approval.    

The key to a successfully developed generic product goes beyond a successful bioequivalency study, product approval, and a successful process validation study. A truly successful generic product is a product that can be made repeatedly, by any trained operator, on any qualified piece of equipment, at any time of the year, without any problems. We like to refer to a formulation and process with such characteristics as “robust”. Spending more time, effort, and planning during the development of any product will certainly generate the type of  “robust” products desired.