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.
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.