FDA News – Page 6 – by Liberty Management Group Ltd.

BASICS OF IMPORTATION – DRUGS

FDA regulates a range of products which includes food (human and animal consumption), medical products (drugs, devices and biological products), radiation-emitting electronic products, tobacco products and cosmetics. All imported shipments of FDA regulated products are evaluated by FDA and needs to comply with same regulations as of domestic products. The products that are offered into U.S including personal items must be declared to U.S. Customs and Border Protection (CBP). CBP will refers all FDA –regulated products to FDA for review. Mostly, importers will hire a custom broker to help them in submitting necessary entry documents and applicable payments to CBP on behalf of the importer. FDA regulated products are refused to enter in US commerce, if they appear to be adulterated, misbranded, or restricted for Sale. Refused products needs to be destroyed or exported from U.S within 90 days.

DRUGS IMPORTATION

FDA will verify compliance with the following requirements at the time of importation.

FDA Drug Establishment Registration
Drug Listing
NDA or ANDA approval (If applicable)
Conducts field examination and analyzes samples of drugs products to make sure they comply with standard and label requirements.
FDA will make sure that the manufacturer is in not is the list of foreign manufacturers who are not in compliance with drug GMP or import alert.

FDA will verify the manufacturer’s registration and listing by comparing the submitted information to CDER’s registration and listing databases. If the information does not match, FDA will ask for additional information or may detain the product. If the product requires a NDA, ANDA or IND and if does not have it, then FDA will subject the product to refusal.

Foreign establishments whose drugs are imported into United States are required to register with FDA and submit their drug listing information of their products intended for marketing in U.S. If the manufacturer has not registered, they need to register with FDA within 5 days after submitting their application. Also all foreign manufacturers are required to identify a U.S. Agent. FDA Drug establishment Registration and drug listing must be submitted to FDA electronically via CDER unless waiver is granted.

Drug products imported into the United States are subject to FDA labeling requirements. FDA will review the drug labels at the time of importation to check whether they are in compliance with FDA regulations. Specific drug labeling requirements are determined by the type of drug product. OTC drugs, prescription drugs, and drugs imported for drug effectiveness studies are subject to specific labeling requirements in addition to the general drug label requirements.

Liberty Management Group , a leading FDA consulting group in the United States provides assistance with drug establishment registration, drug listing and label review and US agent service for foreign drug establishment firms.

Sudha S

Regulatory Consultant

Mail: office@libertymanagement.us

www.fdahelp.us

NATIONAL DRUG CODE (NDC) – AN OVERVIEW

According to the Drug listing act of 1972, all registered drug establishments must provide the current list of all drugs manufactured, processed, prepared, propagated, compounded or processed for commercial distribution in their facility to FDA. These drugs products are identified and reported by using a unique three segment number called National Drug Code (NDC), which serves as universal product identifier for human drugs.

NDC number is a unique 10-digit, 3–segment numeric identifier assigned to each drug listed under Section 510 of FD&C act. Each NDC number identifies the labeler, product and the trade package size of the drug.

The first segment of NDC is known as labeler code, which is a unique 5 digit number assigned by FDA to each establishment that manufactures (including contract manufacturers, re-packers or re-labelers) or distributes (under its own name- Private label distributor).
Second segment, which is the product code, identifies the specifications (strength, dosage form and formulation) of a drug for a particular manufacturer. This denotes that different formulations or different strengths of the same formulation should be assigned different product codes.
The third segment, the package code, classifies package sizes and types. The second and third segments of NDC should be assigned by the labeler. The NDC will be in one of the following configurations: 4-4-2, 5-3-2, or 5-4-1.

NDC Labeler code request to FDA should be submitted in SPL (structured Product Labeling) format via FDA ESG (electronic submission gateway). Labeler is responsible for each NDC directory entry submitted through SPL files. Entry in NDC directory doesn’t indicate that FDA approved or verified the information of the drug. Assignment of NDC number to non-drug products is strictly prohibited. Under FD&C act, registration of a drug establishment or assignment of NDC number does not denote that FDA’s approval of the company or its products.

Even though NDC number is a mandatory requirement, but it is not required to appear on all drug labels and including the label of any prescription drug carton given to a consumer. However, if the same drug product that are sold or used in the hospitals are required to put bar code on their products.

NDC Directory does not include animal drugs, blood products, API (Active Pharmaceutical Ingredients), drugs manufactured exclusively for a PLD, or drugs that are marketed as a part of a kit or combination product or inner cover of a multi-level packaged product not marketed separately.

Liberty Management Group Ltd, provides assistance with drugs establishment registration , NDC labeler code request, Drug Listing and US agent service to foreign facilities.

Sudha S

Regulatory Consultant

Mail: office@libertymanagement.us

http://www.fdahelp.us

ACTIVE PHARMACEUTICAL INGREDIENT (API)

According to FDA, an active pharmaceutical ingredient is defined as “any substance or mixture of substances intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient in the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body.”

API is the part of a drug that creates its effectiveness. In some cases, for example in combination therapies there may be multiple active ingredients to treat different symptoms in various ways.

All drugs are manufactured with two main components one: the API which is the main ingredient and others are called inactive ingredients also known as excipients which helps to deliver the medication into the system. Inactive ingredients are components of a drug product that do not surge or affect the medicinal action of the active ingredients. Inactive ingredients are added during the manufacturing process of the pharmaceutical products. Even though inactive ingredients don’t have any therapeutic effects, they are important and necessary components for any medication which plays an important role in drug composition, absorption, delivery and much more.

Manufacturers are using certain standard to determine the potency of the API in each drug. However it varies from one manufacturer to another. But all the manufacturers are required to register their manufacturing establishment with FDA and prove the effectiveness of their drugs through clinical trials.

Under Section 510 of FD&C Act, all firms that manufacture or processing of human drugs are required to register with FDA. The “manufacture” includes the manufacture, prepare and propagation drugs, drug compounding or processing of a drug. The scope of drug manufacturing include drug analysis, active pharmaceutical ingredient (API), final dosage form (FDF), analytical testing, repackaging or relabeling of any drug.

All API manufacturers are required to register their establishment and list their drugs with FDA. API drug manufacturers needs to submit their registration to FDA through Electronic Submission Gateway (ESG) by creating Structured Product Labeling (SPL) files API manufacturer’s drug establishment registration can be verified at https://www.accessdata.fda.gov/scripts/cder/drls/getdrls.cfm and listing can be verified at https://www.accessdata.fda.gov/scripts/cder/ndc/index.cfm

Liberty Management Group Ltd, provides assistance with API drugs establishment registration , NDC labeler code request, Drug listings and US agent service to foreign facilities.

Sudha S

Regulatory Consultant

Mail: office@libertymanagement.us

www.fdahelp.us

GENERIC DRUGS – AN OVERVIEW

A generic drug is a medicine created to be the equivalent to an already marketed brand-name drug in dosage form, safety, strength, route of administration, feature, physical characteristics, and intended use. The similarities between generic drug and brand-name medicine helps to demonstrate bio-equivalence, which shows that a generic medicine works in the same way and gives the same clinical benefit as its brand-name type. In other words, generic medicine can be taken as an equal substitute for its brand-name equivalent. FDA Generic Drugs program conduct inspections of manufacturing plants every year and monitor the drug safety after it has been approved and marketed.

Even though generic drugs and brand-name drugs share the same active ingredients, safety, strength, efficiency and the intended use, the trademark laws in the United States do not allow them to have the same look exactly like other drugs which is already on the market.

Cost difference between Generic medicine and Brand-name medicine

Companies that develop new drugs, like other new products are protected by patents that restrict other companies from manufacturing and marketing the same drug. The patent protects the company’s investment in developing the drugs by giving the sole right to market the drug till the patent is in effect. FDA allows certain period of marketing exclusively the brand-name medicine till the patents and marketing exclusive rights expire. After that, it approves the generic version of the same drug. Generic drugs cost less than their brand-name equivalent because they do not need to repeat animal and clinical studies that were required for brand-name drugs to demonstrate its safety and efficiency. This is also known as “abbreviated new drug application.” The competition between the brand-name drug and multiple generic drugs is the main reason for low-cost generic drug.

Demonstration of ANDA

ANDA must demonstrate the generic medicine is equivalent to its brand-name counter part by the following ways.

Contain the same active ingredients as the brand-name drug. Active ingredients make the drug effective against the disease or condition it is treating. Inactive ingredients may vary.
Be identical in strength, dosage form and route of administration. If the brand-name drug is a capsule and is taken orally, so is the generic.
Treat the same medical condition.
Be absorbed into the bloodstream at a similar rate and over the same period of time.
Meet the same requirements for identity, strength, purity and quality.
Be manufactured under the same strict standards that FDA demands of brand-name drugs.

FDA will make sure that the medicines both generics and brand- name sold in the United States are safe and effective by conducting testing in its laboratories or through research contract and grants. Also FDA encourages physicians and consumers to notify FDA of any adverse side effects when using the drugs and medical devices which FDA regulates by reporting them at MedWatch .

Liberty Management Group , a leading FDA consulting firm in the United States provides assistance with drug establishment registration, drug listing and label review.

Sudha S

Regulatory Consutltant

Mail : office@libertymanagement.us

http://www.fdahelp.us

CERTIFICATE TO FOREIGN GOVERNMENT (CFG)

Certificate to Foreign Government (CFG) is document prepared by FDA issued for legally marketed devices in the U.S that are in compliance with the regulations of FD&C act.

Medical devices that are legally marketed in the United States can be exported to anywhere in the world without getting approval from FDA. Although FDA does not restrict the export of legally marketed, certain importing countries require a certification from FDA stating that the firm, or its devices are in compliance with U.S. FDA regulations. Foreign government will ask for official assurance that the products exported to their countries are in compliance with US FDA regulations such Good manufacturing Practice (GMP) requirements. In that cases, U.S companies can request a certificate to foreign government (CFG) also known as Certificate of Free sale to FDA.

The certificate to foreign government (CFG) is a self-certification process. By completing the required form, a firm confirms that it is registered with FDA and listed their device with FDA, that each product is legally marketed in the U.S. and is not the subject of an open recall, that all facilities involved in the manufacturing process are complying with the FDA’s regulations, and that each product is being exported from the U.S.

Requirements to get the Certificate to Foreign Government (CFG)

The manufacturing facility must have a valid medical device establishment registration
All devices must be listed with FDA
The devices must have cleared Premarket notification (510K) or Premarket Approval (PMA) unless it is exempted by the regulation.
The device should meet all the medical device labelling requirements as of 21 CFR 801 and 809.
The device should be manufactured in accordance with 21CFR 820 also known as Good Manufacturing practice unless it is exempted by the regulation.

Certificate to Foreign government can be requested through CECATS system. It is a voluntary electronic system that allows the manufacturers and initial importers to request export documents online. CECATS can be accessed by logging into FDA Furls account.

The fees for export certificate from CDRH is $175 for the first certificate and $85 each for additional certificate upon the request from the customer.

Liberty Management Group, a leading FDA consulting firm provides assistance with FDA Medical device registration, device listing and certificate to foreign government application.

Sudha S

Regulatory Consultant

Mail : office@libertymanagement.us

http://www.fdahelp.us

OVER-THE-COUNTER (OTC) DRUG PRODUCTS

Over-the-Counter drugs (OTC) also known as nonprescription drugs are medications sold directly to consumers without a prescription from a physician. OTC drugs are in general considered as safe and effective for use by the consumers without getting treatment from a healthcare professional. There are more than 300,000 OTC drugs are marketed with about 800 active ingredients.

Although there are more than 80 therapeutic categories of OTC drugs, starting from acne products to weight management drugs, FDA is not approving OTC products, but Center of Drug Evaluation and Research (CDER) ensures that OTC drugs are properly labeled and its ingredients listings. For each category, FDA developed an OTC drug monograph and published in the Federal Register. OTC drug monograph provided guidance which covers doses, acceptable ingredients, formulations and labelling requirements. When the company adheres to OTC monograph, it can make and market an OTC drugs without FDA’s pre-approval. OTC monographs defines the safety, efficiency and labeling of all OTC active ingredients. The drugs for which the active ingredients is not OTC monograph, has to apply for New Drug Application (NDA) or Abbreviated New Drug Application (ANDA).

FD&C acts requires firms that manufacture, contract manufacture, repack or re-label or salvaging of OTC drugs in the United States or that are offered for import in the U.S are required to register with FDA and renew their registration annually. Also domestic and foreign establishments must list all drugs that they manufactured, prepared, propagated, compounded, or processed for commercial distribution in the U.S. Foreign firms are required to identify a U.S agent and importers at the time of registration.

FDA Drug establishment registration needs to be submitted electronically using Extensible Markup Language (XML) files in the Structured Product Labeling (SPL) format. The firms must use FDA’s Electronic Submission Gateway (ESG) to submit SPL files.

Private Label Distributors (PLD) are not required to register their establishment with FDA, however they have to apply for their own Labeler code and list their drugs with FDA. FDA has a released a list of summary of registration and listings requirements for the manufacture or distribution of human pharmaceuticals, which can be seen at https://www.fdahelp.us/Pdf/Drug.pdf

Drug establishments that are registered with FDA must list all the products they manufacture for commercial distribution under their own labeler code, which includes the API manufacturers, bulk manufacturers, contract manufacturers, re-packers and re-labelers.

FDA has published a regulation establishing standardized content and format for the labeling of OTC drug products (Drug Facts labeling). The Drug Facts labeling for OTC drug products is intended to make it easier for consumers to read and understand OTC drug product labeling and use OTC drug products safely and effectively. All drugs or drug products in finished package form is considered as misbranded if it does not comply with FDA labeling requirements.

Liberty Management Group provides assistance with drug establishment registration, drug listing and label review.

Sudha S

Regulatory Consultant

Mail: office@libertymanagement.us

http://www.fdahelp.us

UNIQUE DEVICE IDENTIFICATION (UDI)

FDA has released a final rule under which all medical devices will be marked with a Unique Device Identifier (UDI) that will appear on the label and package of a device which is used to identify the devices through their distribution and usage of it. UDIs should be on the device labels in both a human-readable format and a machine-readable format (e.g., a barcode) unless the rule provides for an exception or alternative. The UDI should be marked directly on the devices that are intended for more than one use and has to be reprocessed before each use.

A UDI consists two parts, Device Identifier (DI) and Product Identifier (PI), where

Device Identifier (DI) is a mandatory, fixed portion of a UDI which identifies the specific version or model of a device and its labeler. Labeler has to apply for New DI if there is any change in version or model of the device.

Product Identifier (PI) which is a conditional and variable portion of a UDI is required to identify the lot or batch number of a specific device , serial number, expiration date, date of manufacture and the distinct identification code(If applicable). PI will change for each lot or batch.

FDA has accredited the following agencies in assignment of UDIs according to the UDI regulations.

GSI – http://www.gs1.org /
Health Industry Business Communications Council (HIBCC) – http://www.hibcc.org /
International Council for Commonality in Blood Banking Automation (ICCBBA – http://www.iccbba.org

Each issuing agency has a unique device identifier (UDI) format that was assessed and approved by FDA as part of its process for accrediting issuing agencies. Any changes to the format of the UDI by an issuing agency must be approved by FDA before implementation.

Device labelers are required to submit information about each device to FDA’s Global Unique Device Identification Database (GUDID), where the public can search and download information from GUDID at AccessGUDID. GUDID has a standard set of basic elements for each device with a UDI, which contains only DI that helps to get the device information in the database. Product Identifiers (PI) are not part of GUDID

Compliance Dates issued by FDA in conjunction with UDI Final Rule are

Class III medical devices which includes stand –alone software – September 24, 2014
Implantable, life supporting and life sustaining devices which includes stand-along software – September 24, 2015
Class III reusable devices that are required to have UDI on the device itself, Class II devices – September 24, 2016
Class II reusable devices that are required to have UDI on the device itself, Class I which includes stand-alone software and Unclassified devices – September 24, 2018
Class I reusable devices that are required to have UDI on the device itself – September 24, 2020
For Class I and unclassified devices manufactured and labeled on or after September 24, 2018 – September 24, 2022
For Finished Class I and unclassified devices manufactured and labeled before September 24, 2018 – September 24 , 2022

Liberty Management Group, a leading FDA consulting group in the United States, provides assistance with UDI account creation, selection of Accrediting agency, GUDID submission.

Sudha S

Regulatory Consultant

Mail : office@libertymanagement.us

www.fdahelp.us

PREMARKET NOTIFICATION 510(K)

A 510(k) or Premarket Notification is the technical document required by the FDA to prove that the device to be marketed in the United States are as safe and effective, that is, substantially equivalent, to a legally marketed device which is not subject to PMA. A person who apply for 510K clearance must compare their device to similar legally marketed devices and create and support their substantial equivalence claims. The legally marketed devices to which uniformity is drawn is known as “Predicate”.

The Submitter cannot market the device until he receives an order from FDA declaring a device substantially equivalent (SE). Once the device is declared as SE, it can be legally marketed in United States. SE determination will be made within 90 days of submission and also based on the information submitted by the submitter. Substantial equivalence is issued with respect to intended use, design, energy used or delivered, materials, chemical composition, manufacturing process, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics of the device. If FDA found out that the device is not substantially equivalent (SE), the submitter has to resubmit another 510K with new information or request a product classification via De Nova Classification process or to submit a premarket approval application (PMA).

Who needs to submit a 510K

The following are the four categories of 510K submitters to the FDA.

Domestic manufacturers who introduce a new device to the U.S market. However only finished device manufacturers who manufacture device according to their own specifications needs to submit 510K, whereas the contract manufacturers are not required to submit a 510K.
Specification developers are required to submit a 510K but not the contract manufacturers.
Re-packers or Re-labelers may be required to submit 510K if they change the labels or any other operations that affect the condition of the device.
Foreign manufacturers/exporters who introduce a new device to the U.S market.

All manufacturers, specification developers of Class II and Class III devices and certain Class I devices are required to follow 21 CFR 820 regulations.

Liberty Management Group, a leading FDA consulting group in the United States, provides assistance with preparation and submission of 510K to FDA, US agent service for foreign facilities, medical device establishment registration and listing with FDA.

Sudha S

Regulatory Consultant

Mial : office@libertymanagement.us

www.fdahelp.us

DMF – DRUG MASTER FILES

A Drug Master File (DMF) is a document submitted by a drug manufacturer to US FDA which is used to provide confidential detailed information about facilities, procedures, or things used in the manufacturing, processing, packaging, and storing of one or more human drugs. A DMF is submitted when more companies work in partnership to manufacture a drug product, which allows the company to protect is its intellectual property rights from its partner while complying with regulatory constraints as well for disclosing of processing procedures.

DMF’s are submitted to support regulatory regulations and prove the quality, safety and effectiveness of a product for getting Investigational New Drug Application (IND), New Drug Application (NDA), Abbreviated New Drug Application(ANDA), another DMF and Export Application. However, DMF submission is NOT a substitute for an IND, NDA, ANDA or Export Application. As per FDA regulation, DMF submission is not required by law, it is solely depends to submitters discretion.

As per FDA, there are five types of DMF’s

Type I : Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)
Type II : Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
Type III : Packaging Material
Type IV : Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Type V : FDA Accepted Reference Information

All DMF submissions must be in the English language which should contain transmittal letter, administrative information about the submission and must include specific information about the DMF type.

All foreign DMF holders are required to appoint an U.S agent, however domestic DMF holders do not need a representative to submit it.

DMF holders should submit an annual report on the same date of their original submission. Annual report should contain all the information including name and address of DMF holder, corporate headquarters, Manufacturing/ processing facility, contact for FDA communication, agents (if any),statement of commitment and signed statement by the DMF holder assuring that the DMF is current.

Starting from May 5, 2018 onwards, new DMFs other that Type III, as well as all documents submitted to existing DMFs excluding Type III are required to submit DMF using Electronic Common Technical Document (eCTD). DMFs that are not submitted through eCTD after May 5, 2018 will be rejected, however for Type III DMFs the requirement will be effective from May 5, 2020 onwards.

Liberty Management Group Ltd, a leading FDA consulting group in the United States, provides assistance DMF eCTD submissions, US agent service, DMF closure and reactivation request submission to FDA.

Sudha S

Regulatory Consultant

Mail: office@libertymanagement.us

http://www.fdahelp.us

GOOD MANUFACTURING PRACTICE (GMP)

Good Manufacturing practices is a quality system which ensure that the products are consistently produced and controlled as per the quality standards. GMP regulation provides guidance for manufacturing, testing and quality assurance to ensure that the manufactured product is safe for human consumption or use.

Implantation of GMP assures that the identity, strength, quality and purity of the products as the consumer cannot detect the safety of the product.

FDA inspects drug manufacturing facilities around the world which includes API manufacturers to check whether these companies implemented drug GMP regulations as per 21 CFR part 211. FDA will consider these drugs as adulterated if the company is not complying with GMP regulations.

Medical Device manufacturers must follow and implement quality system to ensure that their products consistently meet all medical device GMP regulations as per 21 CFR part 820. This quality system regulation is applicable to all finished device manufacturers who are planning to do commercial distribution in US. As per 21 CFR 820.3(i) a finished device is any type of device or attachment to any device that is fit for use or capable of working, whether or not it is packaged, labeled, or sterilized.

FDA has classified certain type of medical devices are exempt for GMP regulations, however it does not exempt the manufacturers of finished devices from GMP requirements.

FDA’s GMP regulation as per 21 CFR 820 is aligned with ISO 13485: 2016 to a greater extent than ISO 9001:2015 which is an internationally recognized quality system.

FDA inspects medical device manufacturing facilities to check whether their establishment is in compliance with 21 CFR 820 regulations. If the company is not in compliance with GMP regulations at the time of inspection, FDA will issue an Establishment inspection Report in observations listed on FDA form 483. It is the company’s responsibility to respond FDA 483 warning letter within 15 days and the response has to include the corrective measures taken by the company and preventive solutions taken to stop the recurrence.

Liberty Management Group, a leading FDA consulting group in the United States, provides assistance with 21 CFR 820 GMP regulations, ISO 13485 : 2016 and FDA 483 warning letters.

Sudha S

Regulatory Consultant

Mail : office@libertymanagement.us

http://www.fdahelp.uss