21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals

21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals

FDA ensures the quality of drug products by carefully monitoring drug manufacturers' compliance with its Current Good Manufacturing Practice (CGMP) regulations.  The CGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product.  The regulations make sure that a product is safe for use, and that it has the ingredients and strength it claims to have.

Code of Federal Regulations (CFR).  FDA's portion of the CFR is in Title 21, which interprets the Federal Food, Drug and Cosmetic Act and related statutes, including the Public Health Service Act.

• 21 CFR Part 314 and Part 600 - Application and licensing submission requirements for new and generic drug applicants.
• 21 CFR Part 210 - Current Good Manufacturing Practice in Manufacturing Processing, packing, or Holding of Drugs.
• 21 CFR Part 211- Current Good Manufacturing Practice for Finished Pharmaceuticals.

21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals

Subpart	Clause
A. General Provisions	-
B. Organization & Personnel	211.22 Responsibilities of Quality control unit
	211.25 Personnel Qualifications
	211.28 Personnel Responsibilities
	211.34 Consultants
C. Building  & Facilities	211.42 Design and construction features
	211.44 Lighting
	211.46 Ventilation, air filtration, air heating and cooling
	211.48 Plumbing
	211.50 Sewage and refuse
	211.52 Washing and toilet facilities
	211.56 Sanitation
	211.58 Maintenance
D. Equipment	211.63 Equipment design, size and location
	211.65 Equipment construction
	211.67 Equipment cleaning and maintenance
	211.68 Automatic, mechanical and electronic equipment
	211.72 Filters
E. Control of components and Drug product containers and closures	211.80 General requirements
	211.82 Receipt and storage of untested components, drug product containers and closures
	211.84 Testing and approval or rejection of components, drug product containers and closures
	211.86 Use of approved components, drug product containers and closures
	211.87 Retesting of approved components, drug product containers and closures
	211.89 Rejected components, drug product containers and closures
	211.94 Drug product containers and closures
F. Production & Process Control	211.100 Written procedures; deviations
	211.101 Charge-in of components
	211.103 Calculation of yield
	211.105 Equipment identification
	211.110 Sampling and testing of in-process materials and drug products
	211.111 Time limitations on production
	211.113 Control of microbiological contamination
	211.115 Reprocessing
G. Packaging & labeling Control	211.122 Materials examination and usage criteria
	211.125 Labeling issuance
	211.130 Packaging and labeling operations
	211.132 Tamper evident packaging requirements for over the counter (OTC) human drug products
	211.134 Drug product inspection
	211.137 Expiration Dating
H. Holding & distribution	211.142 Warehousing procedures
	211.150 Distribution procedures
I. Laboratory Controls	211.160 General requirements
	211.165 Testing and release for distribution
	211.166 Stability testing
	211.167 Special testing requirements
	211.170 Reserve samples
	211.173 Laboratory animals
	211.176 Penicillin contamination
J. Records & reports	211.180 General requirements.
	211.182  Equipment cleaning and use log
	211.184 Component, drug product container, closure, and labeling records
	211.186 Master production and control records
	211.188 Batch production and control records
	211.192 Production record review
	211.194 Laboratory records
	211.196 Distribution records
	211.198 Complaint files
K. Returned and salvaged drug products	211.204 Returned drug products
	211.208 Drug product salvaging

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Pre-Launch Activities Importation Requests (PLAIR)

Pre-Launch Activities Importation Requests (PLAIR)

USFDA’s PLAIR program allows the foreign drug product manufacturer for the importation of an unapproved finished dosage form drug product in preparation for market launch. [Based on anticipated approval of a pending new drug application (NDA) or an abbreviated new drug application (ANDA)].

An overseas manufacturer can import unapproved finished dosage form drug product into the US after the PLAIR has been granted and the Division of Import Operations has been notified of the entry number.

Typically, the PLAIR approval process will take approximately 10 business days from the date of submission; however, the processing time may be longer or shorter, depending on the number of requests received by FDA and other aspects of the request.

A PLAIR amendment can be submitted after the PLAIR has been granted. A PLAIR amendment may take up to 1- 2 business day(s) to process, however, the processing time may be shorter or longer, depending on the number of amendments received by FDA.

Important Facts to Remember

A PLAIR can only be submitted for an original pending application for unapproved finished dosage drug product (no more than 60 days prior to anticipated approval or goal date). It does not apply to approved drug applications with a pending supplement.

A PLAIR can only be submitted for an unapproved finished dosage form drug product (not for API or a bulk drug ingredient).

The PLAIR request should be submitted by the sponsor or the applicant holder on firm’s letterhead.

Before submitting a PLAIR, foreign drug product manufacturer must ensure the actual quantities planned to import.

The quantity of drug product imported into the US must match with the quantity stated in the original PLAIR submission.

The PLAIR request should be submitted only to the email address, CDER-OCPLAIR@fda.hhs.gov, at least one month before the proposed arrival date of the shipment to allow sufficient time to process the request but no more than 60 days prior to anticipated approval.

FDA won’t accept PLAIR requests from distributors, consignees, etc…

A PLAIR may be denied for one or more reasons, including but not limited to:

·       PLAIR was submitted earlier than 60 days of expected approval or decision date.

·       Foreign manufacturer does not have a qualifying facility inspection.

·       Foreign manufacturer is not within GMP compliance.

·       Deficiencies noted in the original application.

Role of U.S. Agent for Importing Food, Drug and Medical Devices in US Market

Role of U.S. Agent for Importing Food, Drug and Medical Devices in US Market

When registering with USFDA for importing food, medical device and drugs, the agency legally insists manufacturing companies located outside of the United States to designate a U.S. Agent for that establishment.  FDA sends communications to U.S. Agent regarding inspections and other regulatory matters, which often require an immediate response.

Information about a foreign establishment’s U.S. Agent is submitted electronically using the FDA Unified Registration and Listing System (FURLS system) and is part of the establishment registration process. Each foreign establishment may designate only one U.S. agent. The foreign establishment may also, but is not required to, designate its U.S. agent as its official correspondent. The foreign establishment should provide the name, address, telephone and fax numbers, and e-mail address of the U.S. agent.

The U.S. agent identified will be required to complete an automated process to confirm that they have agreed to act as the U.S. agent. The automated process will forward an email verification request to the U.S. agent. They will be requested to confirm her/his consent to act as a representative/liaison on behalf of the foreign establishment. If the U.S. agent denies consent (or does not respond within 10 business days), the Official Correspondent/Owner Operator of the foreign establishment will be notified and must designate a new U.S. agent to satisfy the regulatory obligation.

Responsibilities of a U.S. agent

The United States agent must reside or maintain a place of business in the United States and may not be a mailbox, answering machine or service, or other place where a person acting as the United States agent is not physically present. The United States agent is responsible for (defined in 21 CFR 207.69):

(1) Reviewing, disseminating, routing, and responding to all communications from FDA including emergency communications;

(2) Responding to questions concerning those drugs that are imported or offered for import to the United States;

(3) Assisting FDA in scheduling inspections; and

(4) If FDA is unable to contact a foreign registrant directly or expeditiously, FDA may provide the information and/or documents to the United States agent. FDA's providing information and/or documents to the United States agent is equivalent to providing the same information and/or documents to the foreign registrant.

Role of an RLD in an ANDA

Role of an RLD in an ANDA

A Reference Listed Drug (RLD) is an approved drug product to which the ANDA applicant must show its proposed generic drug is the same with respect to active ingredient(s), dosage form, route of administration, strength, labeling and conditions of use, among other characteristics. Also in evaluating drug product formulation and inactive ingredients ,an ANDA applicant must compare its proposed generic drug to the RLD’s formulation.

RLD play an important role in the generic drug development process.FDA requires many rigorous tests and procedures to assure that the generic drug can be substituted for the brand name drug. The FDA bases evaluations of substitutability, or “therapeutic equivalence” of generic drugs on scientific evaluations. By law a generic drug product must contain the identical amounts of the same active ingredient(s) as the brand name product. Drug products evaluated as “therapeutically equivalent” can be expected to have equal effect and no difference when substituted for the brand name product.

Pharmaceutical products - Stability study & Mass balance concerns

Pharmaceutical products - Stability study & Mass balance concerns

Mass Balance concept  Assay of parent Product + % impurities ~ 100%

Mass balance is the process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error. In other words Mass balance correlates the measured loss of potency (i.e assay) to the measured increase in the amount of degradation products. If the loss in potency can be reasonably accounted for by the amount of degradants measured, then mass balance is achieved.

Mass balance is to be achieved at least up to 95% level.

 With respect to an analytical method, the term 'mass balance' divulge to its ability to analyse the degradation products of a pharmaceutical product. The assessment of degradation in pharmaceutical products involves two aspects of analytical testing.

1.   Availability of specific or selective analytical method for accurate assay testing of pharmaceutical product, in order to measure any loss.

2. Availability of specific or selective analytical method for quantification of all the degradation products formed. Ideally, when degradation occurs, the measured amount of potency  loss should correlate the increase in degradation products. This correlation is referred to as “mass balance”

 For example, a 25% assay drop of potency (i.e assay) and only 8% increase in degradation products, it is likely that additional degradation products formed are not accurately determined by the given method.

A method is considered to have 'good' mass balance if:

v It can quantify the loss in amount of drug molecule due to degradation (which should result in a lower assay value),

v It can detect and quantify the degradation products formed during degradation of the drug molecule, and

v The amount of the drug lost is equal to the amount of degradation products formed.

Mass balance issue can arise due to following reasons

v Poor understanding of degradation pathways of a parent drug

v Inadequate/poorly developed analytical method.

Unknown degradation products could be toxic and can affect safety and efficacy of the pharmaceutical product, so it is noteworthy to have methods that detect all major degradation products. In short, safety is the prime aspect for the study of mass balance.