Interview Questions and Answers for Formulation Development

What is a Pre-formulation study?

Pre-formulation study is a group of studies that focus on the physicochemical properties of a new drug candidate that could affect the drug performance and the development of a dosage form.

Which parameters are found in the Pre-formulation study?

Appearance, Molecular weight, Solubility, pH, Hygroscopicity, Flowability, Bulk density, Incompatibilities, etc.

What is BCS classification?

The Biopharmaceutical classification system is a system to differentiate drugs on the basis of their solubility and permeability.

Why BCS classification is important?

BCS predicts in vivo performance of drug products from in vitro measurement of solubility and permeability.

What is the application of the Henderson-Hasselbalch (HH) equation?

The henderson-Hasselbalch (HH) equation is frequently used to determine the pH of a solution.

Can you explain your experience in formulation development?

I have 5 years of experience in formulation development. In my previous role, I worked on various projects involving the development of solid, liquid, and semi-solid dosage forms. I have hands-on experience in formulating and optimizing formulations, conducting stability studies, and implementing scale-up processes."

When is the intermediate stability study omitted?

If 30°C ± 2°C/, 65% RH ± 5% RH is the long-term (real-time) condition, there is no intermediate condition.

What is stress testing?

• Stress testing of the drug substance can help identify the likely degradation of products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating the power of the analytical procedures used.
• Stress testing will likely be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing), and humidity (e.g., 75% RH or greater).

Which amount of Povidone is used as a binder?

2-5%

How do you approach formulation development projects?

When approaching formulation development projects, I begin by thoroughly understanding the target product profile and the desired therapeutic effect. I then conduct a comprehensive literature review to gather relevant information about similar formulations and technologies. Next, I design a systematic experimental plan to optimize the formulation parameters, considering factors such as solubility, stability, bioavailability, and manufacturing feasibility. Throughout the process, I closely collaborate with cross-functional teams and utilize scientific tools to ensure successful formulation development.

What is TGA?

Thermo gravimetric analysis is a method of thermal analysis in which the mass of a sample is measured over time as the temperature changes.

What’s the impact of TGA on formulation development?

• Provides information about physical phenomena (phase transition, absorption, desorption), chemical phenomena (chemisorptions, thermal decomposition), and solid-gas reactions (oxidation, reduction).
• Characterize and quantify the moisture content.
• Decomposition mechanism for various polymeric preparations.
• Prediction of stability of the drug.

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What is RLD?

A Reference Listed Drug (RLD) is an approved drug product to which new generic versions are compared to show that they are bioequivalent.

Which information is available in RLD?

Qualitative formulation, Coating materials, Packaging materials, Storage condition etc.

Which parameters are determined in the pre-formulation study?

Molecular weight, Hygroscopicity, Solubility, pH, Storage condition, Incompatibility etc.

Why molecular weight determination is needed for generic drug development?

To determine the factor of an Active ingredient.

Can you discuss your experience with regulatory guidelines and documentation?

I have a strong understanding of regulatory guidelines such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the United States Food and Drug Administration (FDA) requirements. I am experienced in preparing and reviewing documentation, including drug master files, investigational new drug applications, and regulatory submissions. I am diligent in ensuring compliance with these guidelines and maintaining accurate records throughout the formulation development process.

What is glass transition temperature (Tg)?

The temperature region where the polymer transition from a hard, glassy material to a soft, rubbery material.

What is pH-dependent solubility and why it’s important?

pH-dependent solubility means the solubility of a substance depends on pH variation. In general, the dissolution of BCS class II drugs is dependent on a wide variety of physiological factors. pH, ionic strength, and buffer capacity are three major characteristics of GI fluids that can affect the rate of drug release.

How do you ensure the quality and stability of formulations?

Quality and stability are paramount in formulation development. I implement robust stability studies to assess the formulation's physical, chemical, and microbiological stability under various storage conditions. I use appropriate analytical techniques to monitor critical quality attributes over time. Additionally, I conduct accelerated and real-time stability studies to determine the product's shelf life and packaging requirements. By following industry best practices, I ensure that formulations maintain their efficacy, safety, and quality throughout their lifecycle.

What do you mean by Hygroscopicity?

Hygroscopicity is the ability of a material to interact with moisture from the surrounding atmosphere.

What type of measurement should be taken for hygroscopic material?

• Relative humidity should be under control (<45%).
• Wet granulation should be omitted.

What do you mean by QbD?

Design a quality product and its manufacturing process to consistently deliver the intended performance of the product.

What are the tools of QbD?

• Quality Target Product Profile (strength, route of administration, PK parameters, Sterility, Purity, Dissolution, Assay)
• Critical Quality Attributes (particle size, distribution, bulk density, moisture content, and which are affect on product purity, strength, stability etc.)
• Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product CQAs
• Design Space
• Control Strategy
• Product Lifecycle Management and Continual Improvement

What do you mean by Technology Transfer?

Transfer of new technology from the originator to a secondary user.

How can identify the physical incompatibilities of pharmaceutical formulation?

Stress testing may identify the physical incompatibilities of new drug formulations.

Which parameters are affected by the Physical and Chemical interaction of Drug-Excipients?

Any physical or chemical interaction between the drug and the excipient can affect the bioavailability and stability of the drug.

Why do we use cellulose derivatives in Oral solid dosage formulation?

To control or modify the drug release profile.

How can overcome the BCS class IV material problems?

BCS class IV drugs are generally not suitable for oral drug delivery or else some special drug delivery technologies such as Nano-suspensions will be needed.

Can you provide an example of a challenging formulation project you worked on and how you overcame it?

One challenging formulation project I worked on involved enhancing the solubility and bioavailability of a poorly water-soluble drug. To overcome this challenge, I employed various approaches such as solid dispersion, lipid-based formulations, and nano-formulations. Through systematic screening and optimization, I identified a solid dispersion formulation that significantly improved the drug's solubility and dissolution rate. I conducted in vitro and in vivo studies to confirm the enhanced bioavailability. This project demonstrated my ability to overcome formulation challenges by employing innovative strategies and leveraging my expertise in formulation technologies.

What is process validation?

Process validation is the analysis of data gathered throughout the design and manufacturing of a product from validation batches to confirm that the process can reliably output products of a determined standard.

What do you mean by Biosimilar (drug)?

A biosimilar is a biological medical product that is almost an identical copy of an original product with the same active substance that is manufactured by a different company.

What is cytotoxicity?

Cytotoxicity is the quality of being toxic to cells.

How can claim the shelf life of a Pharmaceutical Product?

Depending on the accelerated and intermediate stability study we can claim the shelf life of a pharmaceutical product. When a product is physically and chemically stable at 6 months of accelerated study and 12 months of intermediate study. We can claim 2 years shelf life. But if found any significant change in 12 months of intermediate study we need to follow up with long-term/real-time study.

What do you mean by forced degradation?

Forced degradation is the degradation of new drug substances and drug products at conditions more severe than accelerated conditions.

What is predictable dissolution?

Predictable dissolution is the in-vitro dissolution study. Which predicts the in-vivo dissolution (drug release) rate?

Can SLS hamper dissolution?

Yes, sometimes SLS can hamper the dissolution rate. Especially dissolution rate of gelatin capsules is especially hampered by SLS.

Which co-solvents are commonly used in oral solution preparation?

Propylene glycol, Glycerol, Ethanol, PEG.

How do you stay updated with the latest advancements in formulation development?

Staying updated with the latest advancements in formulation development is crucial for success in this field. I actively participate in conferences, seminars, and workshops related to formulation development. I also subscribe to reputable scientific journals and publications, ensuring that I am aware of emerging technologies, novel excipients, and regulatory updates. Additionally, I am part of professional networks and engage in discussions with colleagues and experts to exchange knowledge and stay abreast of the latest developments.

What are common buffer salts used in oral solution preparation?

Acetates (acetic acid, sodium acetate), 1-2%

Citrates (citric acid, sodium citrate), 1-5%

Phosphates (sodium phosphate, disodium phosphate), 0.8-2%

What antioxidants are commonly used for aqueous and oil bases solution preparation?

• For aqueous solution: Sodium sulfite, Sodium metabisulfite, Sodium formaldehyde sulfoxylate, and Ascorbic acid.
• For oil base solution: Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), and Propyl Gallate.
• Typically antioxidants are employed in low concentrations (< 0.2% w/w).

What types of drug-excipient interactions occur?

• Physical interaction (Complexation, Adsorption, Solid dispersion).
• Chemical interaction (Oxidation, Isomerization, Photolysis, Polymerization).
• Biopharmaceutical interactions (Premature breakdown of enteric coat, Increase in gastrointestinal motility, Interactions due to adjunct therapy).

For which drugs disintegration test is exempted?

Modified or delayed release drugs

What is the HLB value? And for which products it’s important?

Hydrophilic-lipophilic balance (HLB) value is a measure of the degree to which it is hydrophilic or lipophilic. It helps in the selection of a proper surfactant. Especially for emulsion and suspension preparation.

• HLB value <10 indicates lipid soluble.
• HLB value >10 indicates water soluble.
• HLB value 1 to 3 indicates anti-foaming agent.
• HLB values 3 to 6 indicate W/O emulsifier.
• HLB values 7 to 9 indicate wetting agent.
• HLB value 13 to 16 indicates detergent.
• HLB values 8 to 16 indicate an O/W emulsifier.

How do you differentiate between Vitamins and Minerals?

Vitamins are organic and can be broken down by heat, air or acid. Minerals are inorganic elements that come from the soil and water absorbed by plants or eaten by animals.

How to determine the difference and similarity factors of two products and what effect on a bioequivalent product?

• Using the mean dissolution values from both curves at each time interval, calculate the difference factor (f1) and similarity factor (f2).
• For curves to be considered similar- f1 values should be close to 0, and f2 values should be close to 100.
• Generally, f1 values up to 15 (0-15) and f2 values greater than 50 (50-100) ensure sameness or equivalence of the two curves.
• At least 12 units should be used for each profile determination.

How do you approach the scale-up of a formulation from the laboratory to commercial production?

When scaling up a formulation, I adopt a systematic approach that involves closely collaborating with manufacturing and engineering teams. I evaluate the impact of scale on critical formulation parameters, such as mixing times, equipment compatibility, and processing variables. I conduct pilot studies to validate the scalability and identify any potential challenges. By close monitoring and adjusting the process parameters, I ensure that the formulation maintains its desired quality attributes during scale-up and successfully transitions from the laboratory to commercial production.

How can ensure that the bioavailability of the drug is not limited by dissolution?

The BCS suggests that for high solubility, high permeability (class 1) drugs and in some instances for high solubility, low permeability (class 3) drugs, 85% dissolution in 0.1N HCl in 15 minutes can ensure that the bioavailability of the drug is not limited by dissolution.

How to measure the bioavailability of a product?

Bioavailability is usually measured by the area under the blood or plasma concentration-time curve (AUC) and the maximum concentration (Cmax) respectively.

Which is identified by PK and PD parameters?

PK describes the relationship between dose, systemic drug concentration and time.

PD describing the relation between systemic drug concentration and the effect vs. time profile.

Why BCS is important for formulation development?

The knowledge of the BCS characteristics of a drug in a formulation can help a formulation scientist to develop a more optimized dosage form based on fundamental mechanistic, rather than empirical information.

Can you discuss your experience with conducting formulation characterization and optimization studies?

I have extensive experience in conducting formulation characterization and optimization studies. I employ various analytical techniques, such as differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and particle size analysis, to assess the physical and chemical properties of formulations. I also utilize the design of experiments (DoE) to systematically evaluate and optimize formulation parameters, such as excipient ratios, processing conditions, and surfactant concentrations. Through these studies, I ensure that the formulation meets the desired specifications and performance criteria.

What is ANDA?

Abbreviated New Drug Application contains data that, when submitted to the FDA's center for drug evaluation and research, review and ultimate approval of generic drug products. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low-cost alternative to the American people.

What is Out of Specification (OOS)?

Is defined as those results of in-process or finished product testing that does not comply with the pre-determined acceptance established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer.

What is Out of Trend (OOT)?

The result does not follow the expected trend, either in comparison with previous results with other stability batches or with respect to previous results collected during a stability study.

What is Bioassay?

is an analytical method to determine the concentration or potency of a substance by its effect on living cells or tissues.

What is a Biomarker?

is defined as a measurable indicator that can be used to a particular disease state or some other biological state of an organism.

What is Precision?

The precision of an analytical procedure refers to the closeness of agreement between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions.

How do you ensure compliance with Good Manufacturing Practices (GMP) during formulation development?

Compliance with Good Manufacturing Practices is a priority in formulation development. I adhere to GMP guidelines throughout the entire formulation development process, from material selection and equipment cleaning to documentation and record-keeping. I ensure that all raw materials and excipients meet the required quality standards and are properly stored and handled. I follow strict procedures for equipment calibration and maintenance. By implementing robust quality control measures, I ensure that the formulation development process is compliant with GMP requirements and facilitates the production of safe and effective pharmaceutical products.

What is Robustness?

refer to the ability of an analytical method to remain unaffected by small, but deliberate variations in method parameters and provide an indication of its reliability during normal usage.

What is TOC?

Total organic carbon (TOC) is a measure of the total amount is of carbon bound in an organic compound and is often used as a non-specific indicator of water quality or cleanliness of pharmaceutical manufacturing equipment.

Can you provide an example of how you have effectively collaborated with cross-functional teams in your previous role?

Answer: "In my previous role, I had the opportunity to collaborate with cross-functional teams on a complex formulation development project. I actively engaged with formulation scientists, analytical chemists, regulatory affairs professionals, and manufacturing experts. We held regular meetings to discuss progress, address challenges, and align our efforts. By fostering open communication and leveraging each team member's expertise, we successfully developed a stable and commercially viable formulation within the defined timelines. This experience reinforced the importance of effective teamwork and highlighted the value of diverse perspectives in achieving project objectives.

What is the Ultraviolet-Visible (UV) spectrophotometer application?

Ultraviolet–visible spectroscopy or ultraviolet-visible spectrophotometer (UV-Vis or UV/Vis) refers to absorption spectroscopy or reflectance spectroscopy in the ultraviolet-visible spectral region. This means it uses light in the visible and adjacent (near-UV and near-infrared (NIR)) ranges. UV/Vis spectroscopy is routinely used in analytical chemistry for the quantitative determination of different analyses, such as transition metal ions, highly conjugated organic compounds, and biological macromolecules. Determination is usually carried out in solutions.

What is stress testing?

• Stress testing of the drug substance can help identify the likely degradation of products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating the power of the analytical procedures used.
• Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater)

What is Viscosity?

The measurement of the resistance of a material to flow. Viscosity can be determined using a viscometer.

What is Zeta Potential?

is defined as the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle. The significance of zeta potential is that its value can be related to the stability of colloidal dispersions (e.g., a multivitamin syrup).

What is Pyrometer?

• A pyrometer is a non-contacting device that intercepts and measures thermal radiation, a process known as pyrometry. This device can be used to determine the temperature of an object's surface.
• Pyrometer is used for many industrial applications to measure non-contact high-temperature measurements. This is also useful for temperature measurement of molten iron & steel.

What is the Reference standard?

It is a standardized substance It is used as a measurement base for similar substances. Where the exact active substances of a new drug are not known. A reference standard provides a calibrated level of biological effects against which new preparations of the drug can be compared. Climate chamber: It allows investigation of the effects of a gradient in temperature and relative humidity on a porous structure. It also used in measuring how much water it collects or releases.

What is predictable dissolution?

Predictable dissolution is the in-vitro dissolution study. Which predicts the in-vivo dissolution (drug release) rate?

What is Drug Master File (DMF)?

A document containing complete information on an Active Pharmaceutical Ingredient (API) or finished drug dosage form. It may be used to provide confidential detailed information about facilities, processes, or sources used in the manufacturing, processing, packaging, and storing of one or more human drugs. It is known as the European Drug Master File (EDMF) or Active Substance Master File (ASMF) and US-Drug Master File (US-DMF) in Europe and the United States respectively.

What are pharmaceutical impurities?

As defined by the United States Pharmacopeial (USP), impurity is “any component of a drug substance that is not the chemical entity defined as the drug substance and in addition, for a drug product, any component that is not a formulation ingredient.”

What is meant by titration? What are the 4 types of titrations?

Titration, is a process of chemical analysis in which the quantity of some constituent of a sample is determined by adding to the measured sample an exactly known quantity of another substance with which the desired constituent reacts in a definite, known proportion.

4 Types of Titration:

1. Acid-base Titrations.
2. Redox Titrations.
3. Precipitation Titrations.
4. Complexometric Titrations.

What parameters are to be checked for method validation?

1. Selectivity/Specificity
2. Precision
3. Accuracy
4. Linearity
5. Range
6. Stability
7. Limit of Detection (LOD) and Limit of Quantitation (LOQ)

What do you mean by UPLC?

Ultra-Performance Liquid Chromatography (UPLC) is an updated version of HPLC.

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