What is formulation development ?
Formulation and Development is a process of fabrication of drug substance (active pharmaceutical ingredient) with inactive pharmaceutical ingredients ( excipients ) to form a drug product which is stable and has patient compliance.
What are the different types of formulations?
- Tablets : Immediate-release, Sustained-release, Delayed-release, Film-coated
- Capsules : Powder, Granule filling
- Pellets : Into tablets or Capsule filled
- Powders : Powder in a bottle
- Oral and Parenteral Liquids : Solutions, Suspensions, Emulsions
- Semi-solids: Creams, Ointments, Gels, Lotions.
What is process development?
It include optimization of various critical process variable during formulation development with
the aid of quality by design approach.2
What are the different processes?
Tablets: wet granulation, direct compression, dry granulation
Capsules: 3 Machine Rotary Die Process, Norton Capsule Machine, Aerogel Capsule Machine
Pellets: Extrusion, spheronization, cryopelletizaition, microspheronization, powder layering
Powders 4: Trituration, pulverization, levigation, lyophilization
Oral and Parenteral Liquids: mechanical stirring, homogenization and sonication
Semi-solids: moulding, trituration, fusion, ointment mills5
How to choose a dosage form for a particular drug substance?
- Age of patient (Pediatric/Geriatric)
- State of disease (acute or chronic)
- Category of disease (Infections, cancer, psychiatrics...)
- Pharmacokinetic parameters (half-life, first pass metabolism, bioavailability)
- Salt form of drug substance
- Cost and duration of therapy.6
How to choose the process?
- Dosage form (as mentioned earlier)
- Properties of drug substance
- Cost and duration of manufacturing process
- Robustness of process
- Regulatory compliance7
What are the Evaluation parameters to be studied?
- Tablets : Appearance, size, shape, hardness, friability, weight variation, assay, content
- uniformity, disintegration, dissolution8
- Plate Process - Using a rotary or reciprocating productive die, Celton Capsule
- Capsules : weight variation, content uniformity, disintegration, dissolution
- Pellets: Physical description, water content, drug retainity, dissolution profile, assay.
- Powders: density, moisture content, angle of repose, flow properties, Particle size.
- Oral and Parenteral Liquids : weight variation, content uniformity, particulate matter, endotoxin test, Pyrogenic test, sterility test, clarity test, rate of sedimentation, electro kinetic, rheology.
- Semi-solids: non-irritancy, rate of penetration, rate of drug release, rheological properties, content uniformity, microbial content preservative efficacy.
What are the considerations to be studied during formulation development?
During formulation development, selection of dosage form is done by considering various factors as stated below.
- Protection from atmospheric oxygen or humidity (coated tablets, sealed ampoules)
- Protection from gastric acid after oral administration (enteric-coated tablets)
- mask the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets, flavored syrups
- For the drug substances that are either insoluble or unstable in the desired vehicle (suspensions)
- To achieve clear liquid dosage forms of substances (syrups, solutions).
- To produce rate-controlled drug action (various controlled-release tablets, capsules, and suspensions
- To provide drug action from skin as topical administration (ointments, creams, transdermal patches, and ophthalmic, ear, and nasal preparations)
- To provide action of the drug into one of the body's orifices (rectal or vaginal, suppositories)
- To achieve systemic administration directly without first pass metabolism (injection, sublingual tablets, suppositories, colon targeted formulations)
- inhalation therapy for nasal and pulmonary disorders (inhalants and inhalation aerosols)11
- After finalizing the dosage form, the following parameters has to be done from initial state to
- marketing of the developed formulation.
Why Preformulation has to be carried out during formulation development?
This is a stage of formulation development in which physicochemical properties of drug
substances are evaluated. It helps in developing a suitable and stable formulation without
any setbacks and it reduces cost and duration of development process. Commonly evaluating
properties are solubility, pKa, log P, excipient compatibility studies, stability, etc...12
How to start the prototype trials?
Prototype trials has to be carried as per pre-defined design of experiments. As per USFDA,design of experiments (DOE) - "it provides a structured, organized method for determining the relationship between factors affecting a process and the response of that process." Design of experiments should be logical, cost effective and conclusion oriented. Statistical approaches has to be used for designing prototype trials. It should be accompanied with quality by design (QbD)
What is QbD ?
QbD is introduced to reduce time and money consumption during formulation development. In quality by design approach, initially QTPP has to be defined for the developing formulation. tquality target product profile (QTPP) is defined based on the properties of the drug substance, characterization of the RLD product, and consideration of the RLD label and intended patient population. Example MR Tablets were designed to achieve all of the attributes in the QTPP. During formulation development critical quality attributes (CQAs) ad critical material attributes (CMAs) has to be defined For Example MR Tablets, physical attributes (size and splitability), assay, content uniformity and drug release.13 tools (like design expert) considering all the CQA and CMA.
What are the parameters will be checked during stability studies?
After attaining suitable dissolution profile (i.e. f1 < 15 and f2 >50), stability of the optimized formulation has to be assessed in comparison with reference listed drug as per ICH Q1 guideline.
Different packages can be used like, blisters, sachets, unit dose container, etc...as per the stability protocol designed. The storage conditions are accelerated (40degC +- 2degC/75% RH +- 5% RH) for 6 months, intermediate (30degC +- 2degC/65% RH +- 5% RH), long term (25degC +- 2degC/60% RH +- 5% RH ) or 30degC +- 2degC/65% RH +- 5% RH based on the climatic zones.
How to evaluate stability data?
A 5% change in assay from its initial value. Any degradation product exceeding its acceptance criterion. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., colour, phase separation, hardness).As appropriate for the dosage form, e.g., failure to meet the acceptance criteria for dissolution for 12 dosage units.
What is Scale up?
If formula is optimized, reproducible and showing satisfactory stability results, scale up has to be done with the final formula (approx.10x level) which depends on cost, availability of equipments. in the facility, and feasibility of the trials. Then samples can be charged for the stability as per the previous section.
What will be performed during process optimization and Validation?
Experiments should be designed as per statistical Process optimization has to be performed as per the predetermined QbD approach. Based on the targeting market (United stated, European stated, Rest of the world), the number of validation batches has to be fixed and performed under cGMP condition with proper batch records in the scale of not less than 100,000 units.
When Exhibit batches will be taken?
as per regulatory requirement exhibit batches has to be performed (not less than 100,000 units) and has to charge for stability after packing in developed packaged materials. Then samples has to be sent for bioequivalence studies.
What is Bioequivalence?
Reference listed drug has to be compared with the developed formulation in humans and should be bioequivalent (in vitro and in vivo correlation). United States Food and Drug Administration (FDA) has defined bioequivalence as, "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."14
When will Filing and Marketing be done?
After compiling the all the documents in the proper formats, based on market (ANDA for US and MAA for EU) will be filed to corresponding regulatory authority. As per the standard duration of the application will be accepted and the product will allowed for marketing.