Suitability Petitions for ANDAs

An ANDA suitability petition is a petition (request) to FDA to permit the filing of an ANDA for a drug that differs from the RLD.  Certain differences between a reference listed drug (RLD) and a proposed generic drug product may be permitted in an abbreviated new drug application (ANDA) if these differences are the subject of an approved suitability petition submitted under section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act, and pursuant to 21 CFR 314.93.  An applicant may submit a suitability petition to the FDA requesting permission to submit an ANDA for a generic drug product that differs from an RLD in its: route of administration, dosage form  (e.g., change from tablet to capsule),  strength, (Congress permitted this type of change but, since the passage of Hatch-Waxman and the advent of the petition process, FDA has not approved this type of change to date because it almost always raises some question of safety or efficacy.) or if it has one different active ingredient in a fixed-combination drug product. An ANDA citing a suitability petition that has not been approved will not be received for review because the application lacks a legal basis for the submission. A generic applicant cannot submit an ANDA for such a product until FDA has approved the related petition. The grounds for FDA approval of such a petition are set out in 21 CFR 314.93(e). The determination that an ANDA will be approved is not made until the ANDA itself is submitted and is reviewed by the Agency. The Food and Drug Administration (FDA) will approve a suitability petition unless, among other reasons, one of the following occurs: 1.            FDA determines that the safety and effectiveness of the proposed change from the reference listed drug (RLD) cannot be adequately evaluated without data from investigations that would be beyond the scope of what may be required for an ANDA. 2.         A drug product is approved in a new drug application for the change requested in the suitability petition. 3.      The suitability petition requests changes to a drug product that trigger the need for pediatric studies under the Pediatric Research Equity Act (Public Law 108-155) to assess the safety and efficacy of that drug product in a relevant pediatric subpopulation that would not be waived by FDA, which renders the proposed product ineligible for approval in an ANDA. 1 FDA will refuse to receive an ANDA citing to a pending suitability petition (or to a suitability petition that was denied) because that ANDA would lack a legal basis for submission. FDA’s office of generic drugs (OGD) is responsible for review of suitability petition requests. FDA’s will approve or deny an ANDA suitability petition no later than 90 days after its submission.

Key Words

ANDA Suitability Petitions/ Petitioned ANDA

Q1 & Q2 Sameness Requirements for Parenteral Generic Product Filings - US Vs EU

Q1 & Q2 Sameness Requirements for Parenteral Generic Product Filings -  US Vs EU

Q1 & Q2 Sameness Requirements -  US Market

In case of Parenteral drug products, ANDA and RLD shall have same qualitative and quantitative composition to active components and generally must contain the same inactive ingredients and in the same concentration as the RLD. However, specific changes (from the RLD drug product) are permitted for certain inactive ingredients (i.e., preservatives, buffers, and antioxidants), which are considered exception inactive ingredients. Applicants should identify and characterize the differences and should submit information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product. This justification is a critical aspect of the exception inactive ingredient allowance and should be provided in the ANDA to support the proposed exception inactive ingredient change.

For all other inactive ingredients, an ANDA whose subject is a parenteral drug product must be qualitatively and quantitatively the same (Q1/Q2 same) as the RLD, with certain allowable differences permitted under 21 CFR 314.94. Before submitting an ANDA, the applicant can submit a controlled correspondence to request a Q1/Q2 evaluation of proposed formulations to minimize the risk of FDA refusing-to-receive the ANDA.

An ANDA concerning an ophthalmic drug product should be Q1/Q2 the same as the RLD with respect to all of its components, or include data from appropriate BE studies. Despite a similar allowance (to parenteral products) provided for ophthalmic drug products in 21 CFR 314.94,FDA has determined that, as a scientific matter, any qualitative or quantitative deviations from the RLD should be accompanied by an appropriate in vivo BE study or studies.

For Otic drug products, differences with respect to the types of inactive ingredients listed in 21 CFR 314.94 are permitted, provided that these differences are identified and characterized and information is submitted demonstrating that these differences do not affect the safety or efficacy of the proposed drug product.

Q1 & Q2 Sameness Requirements -  EU Market

Generic and reference products shall have same qualitative and quantitative composition only to active components and not to the other ingredients of the product. However, difference in excipient composition or differences in impurities must not lead to significant differences as regards safety and efficacy.

Reference

USFDA Guidance to Industry - Controlled Correspondence Related to Generic Drug Development

USFDA Guidance to Industry - ANDA Submissions – Refuse-to-Receive Standards

Procedure for marketing authorization – Chapter 1

What is European Public Assessment Report (EPARs) and Periodic safety update reports (PSURs)?

What is European Public Assessment Report (EPARs) and Periodic safety update reports (PSURs)?

A European public assessment report (EPAR) is published for every human or veterinary medicine application that has been granted or refused a marketing authorisation. This follows an assessment by EMA of an application submitted by a pharmaceutical company in the framework of the Central authorisation of medicines. An EPAR provides public information on a medicine, including how it was assessed by EMA. The EPAR is referred to in Article 13(3) of Regulation (EC) No 726/2004, which requires EMA to publish a public assessment report for each centrally authorised medicine together with a public-friendly overview. EMA has developed the EPAR concept over time to ensure that it delivers a usable, transparent and appropriately detailed body of information. The EPAR content and structure have therefore evolved over time and may be further developed in future. An important role of the EPAR is to reflect the scientific conclusions of the relevant EMA committee at the end of the assessment process, providing the grounds for the committee opinion on whether or not to approve an application. All EPARs are published on the EMA website and can be viewed under human medicines and veterinary medicines. Periodic safety update reports (PSURs) are pharmacovigilance documents intended to provide an evaluation of the risk-benefit balance of a medicinal product at defined time points after its authorisation. The objective of the PSUR is to present a comprehensive and critical analysis of the risk-benefit balance of the product, taking into account new or emerging safety information in the context of cumulative information on risk and benefits EMA and national competent authorities assess information in PSURs to determine if there are new risks identified for a medicine and/or if its risk-benefit balance has changed. A PSUR assessment can determine if further investigations on a specific issue are needed, or if an action is necessary to protect public health (e.g. an update of the information provided to healthcare professionals and patients). Marketing authorisation holders (MAHs) are legally required to submit PSURs, in line with Regulation (EU) No 1235/2010, Directive 2010/84/EU and Commission Implementing Regulation (EU) No 520/2012.

Marketing Authorizations (MA) Validity and Renewal in EU – Interesting Facts

Marketing Authorizations (MA) Validity and Renewal in EU – Interesting Facts

A marketing authorisation is required before medicinal products can be marketed in the EU. A marketing authorisation granted by the European Commission is valid in all Member States (centralised marketing authorisation). A marketing authorisation granted by a National Competent Authority (“NCA”) in a Member State is valid only in that Member State (national marketing authorisation).

After a marketing authorisation has been granted, the holder of the authorisation shall inform the Agency of the dates of actual marketing of the medicinal product for human use in the Member States, taking into account the various presentations authorised.

The marketing authorisation holder shall notify the Agency if the product ceases to be placed on the market of a Member State, either temporarily or permanently. Such notification shall, other than in exceptional circumstances, be made no less than two months before the interruption in the placing on the market of the product. The marketing authorisation holder shall inform the Agency of the reasons for such action in accordance with Article 14b.

According to Article 14 of Regulation (EC) No 726/2004 and Article 24 of Directive 2001/83/EC the initial standard marketing authorisation is valid for five years. Such marketing authorisation may be renewed on the basis of a re-evaluation of the benefit-risk assessment. To this end, the MAH shall provide the Agency or the NCAs with a consolidated version of the file in respect of quality, safety and efficacy, at least 9 months before the marketing authorisation ceases to be valid. The start of the evaluation process by the CHMP, more precisely by an elected Rapporteur and Co-rapporteur, shall be the earliest starting date possible, and it can take up to 120 days of active time.

Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the Commission decides, on justified grounds relating to pharmacovigilance, including exposure of an insufficient number of patients to the medicinal product concerned, to proceed with one additional five-year renewal.

Any authorisation which is not followed by the actual placing of the medicinal product for human use on the Community market within three years after authorisation shall cease to be valid.

When an authorised medicinal product previously placed on the market is no longer actually present on the market for three consecutive years, the authorisation shall cease to be valid.

The marketing authorisation holder shall notify the Agency forthwith of any action the holder takes to suspend the marketing of a medicinal product, to withdraw a medicinal product from the market, to request the withdrawal of a marketing authorisation or not to apply for the renewal of a marketing authorisation, together with the reasons for such action.

Reference:

1.           Regulation (EC) No 726/2004 Of The European Parliament And Of The Council ( of 31 March 2004) - Laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.

2.         Directive 2001/83/EC Of The European Parliament And Of The Council (of 6 November 2001) -  On the Community code relating to medicinal products for human use.

USFDA’s User Fee Programs - PDUFA/MDUFA/GDUFA/BsUFA/ADUFA/AGDUFA

The User Fee programs help the Food and Drug Administration (FDA) to fulfill its mission of protecting the public health and accelerating innovation in the industry. The Office of Financial Management (OFM) is responsible for the financial management of the user fee programs.

US FDA’s User Fee programs help FDA to hire and retain sufficient numbers and types of technical and scientific experts to   efficiently conduct reviews of drug/device applications and improving the predictability of review processes.

FDA’s User Fee programs

PDUFA - Prescription Drug User Fee Act

MDUFA - Medical Device User Fee Act

GDUFA - Generic Drug User Fee Act

BsUFA - Biosimilar User Fee Act

ADUFA – Animal Drug User Fee Act

AGDUFA – Animal Generic Drug User Fee Act

What is the difference between them? Topics related to Pharmaceutical Production, Quality Assurance, Quality Control, Regulatory Affairs, Engineering, Microbiology, Formulations, R&D, GMPs, Regulations, Inspections

What is the difference between a strip pack and a blister pack?

The difference between a strip pack and a blister pack is that a strip pack doesn’t have thermoformed or cold formed cavities; the strip pack is formed around the tablet or capsule when it is dropped to the sealing area between sealing moulds. Blister packing contain PVC/PVDC foil in one side and   Aluminum foil in the other side, whereas in Strip packs contains aluminum foil in both sides. Advantage: The Al/PE laminated film has the same protective property as cold forming aluminum film, that perfectly protects the medicine from moisture, light and oxygen. Disadvantages: Slower speed of production compared to thermoforming blister pack; Because it doesn’t have pre-formed cavities, the packaging area for each item is larger than the blister pack.

What is the difference between Calibration and Validation?

Calibration is the demonstration that, a particular instrument or device produces results within specified limits by comparisons with those produced by a reference or traceable standard over an appropriate range of measurements. Whereas Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria. In calibration performance of an instrument or device is comparing against a reference standard. But in validation such reference standard is not using. Calibration ensures that instrument or measuring devices producing accurate results. Whereas validation demonstrates that a process, equipment, method or system produces consistent results (in other words, it ensures that uniforms batches are produced).

What is the difference between Disintegration and Dissolution?

Disintegration is a disaggregation process, in which an oral dosage form falls apart in to smaller aggregates (Disintegration time is the ‘break up’ time of a solid dosage form). Whereas dissolution is a process by which solid substance enters in the solvent to yield a solution. It is controlled by the affinity between the solid substance and the solvent. In other word disintegration is a subset of dissolution.

What is the difference between FDA Form 482 and 484?

FDA Form 482 – Notice of Inspection Form 482 is an official notice of FDA inspection. This document gives FDA the authority to enter a facility and inspect as per section 704 of the FD&C act. FDA Form 484 – Receipt for Samples Form 484 is an acknowledgement of samples received by FDA as per section 704 of the FD&C act.

Form 483 and Warning Letter’s are two serious documents issued by USFDA which are very different in regulatory and legal prospective. “FDA 483 lists observations made by the FDA representative during the inspection of a facility. They are inspectional observations, and do not represent a final Agency determination regarding firms compliance.” The FDA-483 can be amended after an inspection by the investigator who issued it and re-issued.   The Warning Letter is a document that usually originates from the FDA-483 observations that have been linked to citations by one or more legal reviews within the Compliance and legal branch of the FDA. A Warning Letter is informal and advisory. It communicates the agency's position on a matter, but it does not commit FDA to taking enforcement action. For these reasons, FDA does not consider Warning Letters to be final agency action on which it can be sued. The Warning Letter is issued by the agency and not the investigator. FDA 483’s Warning Letter The Form 483 is issued for inspectional observations. It lists the alleged deficiencies or issues of non-compliance in the manufacturer’s quality system. Warning letters are issued for violations of “regulatory significance” (Significant violations are those violations that may lead to enforcement action if not promptly and adequately corrected). The Form 483 is issued by the inspection team alone. The warning letter is issued from a higher level FDA official or officials.  Bad inspections lead to Form 483s. Warning letters usually result from multiple lacking responses to issued 483s, or other issues much more serious that require quick attention/escalation.

What is the difference between Hard Gelatin and Soft Gelatin Capsules?

Both the hard and softgel capsules are made of gelatin.Thus the difference between these two types of capsules lies in the design and manufacturing technology which are detailed below. Hard Gelatin Capsule Soft Gelatin Capsule Made of hard gelatin Made of soft gelatin Produced in two halves consisting of a body and cap Produced as a single piece of gelatin, rather than two halves attached Mainly used for filling dry and powdered content Mainly used for oil-based formulations They’re manufactured using different machines, for shell production and encapsulation. A different process is employed in manufacturing Manufacturing and filling is done using the same machine, as part of a single process Hard gel capsules usually are cylindrical Can be made in a variety of shapes such as the oval, round, tube-like, fish-like, etc. These are made of only hard gelatin, colorings, plasticizer and titanium dioxide Lots of ingredients are used, i.e. soft gelatin, plasticizer, sugars, preservatives, colorings, opacifier, etc. The ratio of gelatin and plasticizer is 1:0.4 The ratio of gelatin to plasticizer is 1:0.8 Available in a range of sizes Size variety is limited

What is the difference between Humidity and Relative Humidity?

"Humidity" and "Relative Humidity" is not the same thing. Humidity means amount of water vapour present in air with respect to total amount of air. Relative Humidity is the amount of moisture in the air 'relative' to the temperature (i.e relative humidity is the amount of moisture in the air compared to what the air can "hold" at that temperature. When the air can't "hold" all the moisture, then it condenses as dew). The relative humidity is a measure of the amount of water vapor in the air (at a specific temperature) compared to the maximum amount of water vapor air could hold at that temperature, and is given as a percentage value. Relative humidity depends on the temperature of the air.

What is the difference between KF and LOD?

In pharmaceuticals, several methods are employed to determine the water content of a substance/product. Among which Karl Fischer Titration (KF) and Loss on Drying (LOD) are most honored and largely reliable methods. Loss-on-Drying (Weight Loss) This method uses the principle of drying a sample of the product and comparing the weight before and after drying. The difference in weight represents the moisture that is in the product. This can be accomplished by using various manner such as drying ovens, infrared balances, and infrared lamps. Whatsoever, the drying conditions are strictly specified. The difference in weight after drying is due to the loss of all evaporated matter, which is taken to represent the moisture content. Repeatability and accuracy of this method solely depend up on the temperature and time controls adopted during testing. The difficulty is that this technique measures all the moisture lost from the sample, which includes not just water but also any other volatile component already present in the sample (like residual volatile solvents) or created by polymerization or degradation of the sample. Karl Fischer (KF) Titration Karl Fischer titration is a very specific determination method which detects and measures only water, including water of crystallization and surface-absorbed water. It is based upon a redox reaction involving water and iodine in the presence of a base, an alcohol, and sulfur dioxide. The water-iodine reaction is dependent upon the presence of water, and therefore the titer of reagent used up in the reaction reflects the amount of water in the sample as there is no other source of water. The KF reagent contains iodine and when it has completely reacted with the total water, excess iodine appears in the solution, causing a color change as well as an electrometric change which can be detected by a double platinum electrode. KF titration measures total water and is not affected by the presence of residual volatile solvents. It has a wide and sensitive range of determination from a water content of 100% to 1 ppm. KF LOD KF is a method, which measures only the water content (i.e. it's water-specific) in a product sample. LOD on the other hand, measures the total change in weight of a material as a result of drying. For some products, components such as alcohol or fat evaporate with the water. Therefore, the LOD method measures both the water and volatile impurities such as those mentioned previously Karl Fischer titration is a chemical method. It involves adding a reagent to the sample to cause a reaction that converts the water in a product to a non-conductive chemical. Loss on Drying compares the weight of a product before and after it is dried. This difference in weight is taken as the percentage of moisture in the product.

What is the difference between mg and IU?

Basically Mg is mass......... IU is effect Milligrams (mg) are a measure of mass(weight). A milligram is one thousandth of a gram. International Units (IU) are a measure based on the biological activity of a substance in the body. These units are arbitrarily set by a committee of researchers commissioned by the World Health Organization. The goal is to provide a measure of the effect on the body a substance will have regardless of its mass. For Ex: 1 IU of Vitamin C is 50 mgs, but 1 IU of insulin is .045 milligrams. That's for the pure crystalline versions of those chemicals: a different preparation or a related chemical may have the same effect using a different amount, and that would also be 1 IU. IU is used for vitamins, hormones, some drugs, vaccines, blood products and similar biologically active substances. Despite its name, the IU is not part of the International System of Units used in physics and chemistry.

What is the difference between Thermoforming and Cold forming Technology in Blister packing?

Thermoforming is a technique that involves heating sheets of PVC prior to insertion into a blister machine. This is typically achieved by passing the sheets between upper and lower heating plates. When a sheet enters a thermoforming blister machine, it is soft and pliable and can be forced to take on the shape of a mold through the application of pressure. In some cases, a mechanical stamp will be used in addition to the application of pressure, particularly when the shape of the mold is difficult or complex. Cold forming is a technique that does not involve any application of heat. Unlike the thermoforming method that uses clear PVC, this technique uses thin sheets of laminate film that contain aluminum. In order to create packaging out of these sheets, a blister machine will typically use a stamp to force it into a form. The aluminum-based film will tend to stretch and retain the shape after the stamp has been removed. This type of blister pack is typically used to contain pharmaceuticals, since the aluminum-based film tends to prevent moisture from entering the packaging.

What is the difference between Warning Letter and Untitled Letter?

If a person or firm violates the Federal Food, Drug and Cosmetic Act (FD&C Act), FDA may give them an opportunity to take voluntary and prompt action to correct the violation before FDA initiates an enforcement action. FDA will issue either a Warning Letter or an Untitled Letter, depending upon the nature of the violation. FDA uses Warning Letters for violations that may lead to enforcement action if they are not promptly and adequately corrected. FDA uses Untitled Letters for violations that are not as significant as those that trigger warning letters. Unlike a Warning Letter, an Untitled Letter does not include a statement warning that failure to promptly correct a violation may result in an enforcement action. An Untitled Letter cites violations that do not meet the threshold of regulatory significance for a Warning Letter. An Untitled Letter differs from FDA warning letter in following aspects. The letter is not titled    The letter does not include a statement that FDA will advise other federal agencies of the issuance of the letter so that they may take this information into account when considering the awarding of contracts. The letter does not include a warning statement that failure to take prompt correction may result in enforcement action. The letter does not evoke a mandated district follow-up. The letter requests (rather than requires) a written response from the firm within a reasonable amount of time (e.g., "Please respond within 30 days"), unless more specific instructions are provided in a relevant Compliance Program. Any appropriate agency compliance official may issue an Untitled letter. Warning Letter VS Untitled Letter Warning Letter Untitled Letter Does not represent official FDA enforcement action Does not represent official FDA enforcement action Includes statement about potential enforcement action Does not include statement about potential enforcement action Intended to induce voluntary compliance with regulations Intended to induce voluntary compliance with regulations Is the most serious communication before the FDA takes enforcement action Less serious than warning letter (still serious!)

What is the difference between ALCOA and ALCOA Plus?

ALCOA and ALCOA Plus are acronyms related to data integrity. When the concept of Data integrity was first introduced in late 90’s, regulatory agencies used the term ALCOA to indicate the main 5 principles of data integrity, which are referring to Attributable, Legible, Contemporaneous, Original and Accurate. Later on the concept of ALCOA Plus introduced to the industry indicating the 5 main principles of data integrity (i.e Attributable, Legible, Contemporaneous, Original and Accurate) plus additional emphasis on the attributes of being complete, consistent, enduring and available.

What is the difference between Contamination and Cross Contamination?

Contamination is the undesired introduction of impurities (of chemical and microbiological nature) or foreign matter, into or onto a starting material or intermediate, API or finished product during: storage, sampling, processing, packing or transport. Whereas Cross contamination is the contamination of a starting material, Intermediate or finished product with another starting material, intermediate or product. Reason for contamination/cross contamination of drug substance/product can vary and caused by multiple factors. Facility constraints, lack of procedures, lack of awareness etc. are the few among them.

What is the difference between Reference Listed Drug (RLD) and Reference Standard (RS) in Orange Book?

Reference Listed Drug (RLD): An RLD is the specific listed drug on which an ANDA applicant relies in seeking approval for its ANDA. Reference Standard (RS): A reference standard (RS) is a listed drug selected by FDA that an ANDA applicant must use in conducting an In-vivo bio equivalence study.

What is the difference between GDUFA and PDUFA?

Both GDUFA and PDUFA are US FDA’s User Fee programs, which help FDA to hire and retain sufficient numbers and types of technical and scientific experts to efficiently conduct reviews of human drug applications (NDA and ANDA) and improving the predictability of review processes GDUFA is related to ANDAs whereas PDUFA is related to NDAs.  GDUFA: Generic Drug User Fee Amendments. The Generic Drug User Fee Act is a law designed to speed access to safe and effective generic drugs to the public, and reduce costs to industry. PDUFA: Prescription Drug User Fee Act  is  a law passed by the United States Congress in 1992 which allowed the Food and Drug Administration (FDA) to collect fees from drug manufacturers to fund the new drug approval process.

What is the difference between Biologics and Bio similar ?

Biologics or biological products are medicines made from living organisms through highly complex manufacturing processes and must be handled and administered under carefully monitored conditions.  Biologic: A biological product or biologic, is a preparation, such as a therapeutic drug, monoclonal antibodies or vaccines, that is made from living organisms (such as microorganisms, animal cell or plant cell). Compared with conventional chemical drugs, biologics are relatively large and complex molecules. They may be composed of proteins (and or their constituent amino acids), carbohydrates (such as sugars), nucleic acids (such as DNA), or combinations of these substances. Patients receives biologics by injection under skin (subcutaneously) or by intravenous infusion and cannot take them orally, since the digestive process break down the biologic and make them ineffective. Bio similar: A Bio similar is similar but not identical to a brand name biologic medicine (reference product). Bio similar has the same mechanism of action, route of administration, dosage form, and strengths as the brand name biologic medicine (reference product). Bio similar is highly similar, but not structurally identical and exact replicas of the brand-name biologic; there can be minor differences in clinically inactive components. Because biologics are more complex than chemical drugs, both in composition and method of manufacture. Since bio similars are not identical, they are not generic versions of the biologic they are copying, but they are affordable alternatives that work similarly and are shown in studies to have equivalent outcomes.