Aflatoxins contamination risks in Pharmaceuticals

Aflatoxin contamination risks in pharmaceuticals

Aflatoxins are naturally occurring fungal metabolites. They are highly toxic compounds and can cause both acute and chronic toxicity in humans and many other animals. Aflatoxins are carcinogenic and genotoxic, they can associated with liver cancer.Aflatoxin is naturally occurring mycotoxin produced mainly by two types of mould, Aspergillus flavus and aspergillus parasiticus. These causative organisms can grow on crops such as peanuts,wheat,corn,beans and rice. Aspergillus flavus is common and wide spread in nature. The occurrence of aflatoxin is influenced by certain environmental  factors, hence the extent of contamination will vary with geographical location. At least 13 different types of aflatoxins are produced in nature with aflatoxin B1,which is considered as most toxic.There are 4 major aflatoxins B1,B2,G1 & G2.The B series contain a cyclopentone ring,instead of a D lactone ring in the G series,this difference being responsible for higher toxicity of B series. Aflatoxin is  recognized as an important food safety risk worldwide, even though it’s potential risks with regards to pharmaceutical industry cannot be ruled out.

Important Facts to Remember……. ·       Aflatoxin, produced by the fungi Aspergillus flavus and A. parasiticus on crops such as maize, peanuts, and tree nuts, are ubiquitous contaminates of the human food supply throughout the economically developing world. ·       Aflatoxin exposures multiplicatively increase the risk of liver cancer. ·       The adverse health consequences of aflatoxins in populations are quite varied, eliciting acute effects, such as rapid death, and chronic outcomes, such as hepatocellular carcinoma.

Complete Response letter (CRL)

Complete Response letter (CRL)

When the USFDA declines to approve an application, it informs the drug company through a complete response letter. These letters systematically document deficiencies that FDA reviewers have identified.

USFDA will send the applicant a complete response letter if the agency determines that they will not approve the application or abbreviated application in its present form for one or more of the reasons given in § 314.125 or § 314.127, respectively.

 (1) Description of specific deficiencies. A complete response letter will describe all of the specific deficiencies that the agency has identified in an application or abbreviated application.

(2) Complete review of data. A complete response letter reflects FDA's complete review of the data submitted in an original application or abbreviated application (or, where appropriate, a resubmission) and any amendments that the agency has reviewed. The complete response letter will identify any amendments that the agency has not yet reviewed.

(3) Inadequate data. If FDA determines, after an application is filed or an abbreviated application is received, that the data submitted are inadequate to support approval, the agency might issue a complete response letter without first conducting required inspections and/or reviewing proposed product labeling.

(4) Recommendation of actions for approval. When possible, a complete response letter will recommend actions that the applicant might take to place the application or abbreviated application in condition for approval.

(b) Applicant actions. After receiving a complete response letter, the applicant must take one of following actions:

(1) Resubmission. Resubmit the application or abbreviated application, addressing all deficiencies identified in the complete response letter.

(i) A resubmission of an application or efficacy supplement that FDA classifies as a Class 1 resubmission constitutes an agreement by the applicant to start a new 2-month review cycle beginning on the date FDA receives the resubmission.

(ii) A resubmission of an application or efficacy supplement that FDA classifies as a Class 2 resubmission constitutes an agreement by the applicant to start a new 6-month review cycle beginning on the date FDA receives the resubmission.

(iii) A resubmission of an NDA supplement other than an efficacy supplement constitutes an agreement by the applicant to start a new review cycle the same length as the initial review cycle for the supplement (excluding any extension due to a major amendment of the initial supplement), beginning on the date FDA receives the resubmission.

(iv) A major resubmission of an abbreviated application constitutes an agreement by the applicant to start a new 6-month review cycle beginning on the date FDA receives the resubmission.

(v) A minor resubmission of an abbreviated application constitutes an agreement by the applicant to start a new review cycle beginning on the date FDA receives the resubmission.

(2) Withdrawal. Withdraw the application or abbreviated application. A decision to withdraw an application or abbreviated application is without prejudice to a subsequent submission.

(3) Request opportunity for hearing. Ask the agency to provide the applicant an opportunity for a hearing on the question of whether there are grounds for denying approval of the application or abbreviated application under section 505(d) or (j)(4) of the act, respectively. The applicant must submit the request to the Associate Director for Policy, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993. Within 60 days of the date of the request for an opportunity for a hearing, or within a different time period to which FDA and the applicant agree, the agency will either approve the application or abbreviated application under § 314.105, or refuse to approve the application under § 314.125 or abbreviated application under § 314.127 and give the applicant written notice of an opportunity for a hearing under § 314.200 and section 505(c)(1)(B) or (j)(5)(c) of the act on the question of whether there are grounds for denying approval of the application or abbreviated application under section 505(d) or (j)(4) of the act, respectively.

(c) Failure to take action.

(1) An applicant agrees to extend the review period under section 505(c)(1) or (j)(5)(A) of the act until it takes any of the actions listed in paragraph (b) of this section. For an application or abbreviated application, FDA may consider an applicant's failure to take any of such actions within 1 year after issuance of a complete response letter to be a request by the applicant to withdraw the application, unless the applicant has requested an extension of time in which to resubmit the application. FDA will grant any reasonable request for such an extension. FDA may consider an applicant's failure to resubmit the application within the extended time period or to request an additional extension to be a request by the applicant to withdraw the application.

(2) If FDA considers an applicant's failure to take action in accordance with paragraph (c)(1) of this section to be a request to withdraw the application, the agency will notify the applicant in writing. The applicant will have 30 days from the date of the notification to explain why the application should not be withdrawn and to request an extension of time in which to resubmit the application. FDA will grant any reasonable request for an extension. If the applicant does not respond to the notification within 30 days, the application will be deemed to be withdrawn.

                

Important Facts to Remember……. ·       Complete response letters will only be issued for applications that are not approved (A Complete Response Letter informs companies that an application is not ready for approval). ·       A complete response letter (CRL) from the FDA delays a product’s entry to the market by an average of 14 months. Companies that receive the letters take an average of seven months just to respond to them. ·       With limited exceptions, the public does not receive a full account of the FDA’s reasons for disapproval because complete response letters are part of unapproved applications that FDA regulations generally treat as confidential. ·       CRL is  designed to help reduce the number of ANDA review cycles, which has significantly decreased the efficiency of the ANDA review and approval process. ·        Agency's Center for Drug Evaluation and Research (CDER) issues the CRL at the end of review process.

EU GMP Annexure -1 (Manufacture of sterile medicinal products) is ‘all set’ for revision

EU GMP Annexure -1 (Manufacture of sterile medicinal products) is ‘all set’ for revision

Annex 1, the primary GMP guidance on sterile manufacturing for Europe and PIC/S member countries is ‘ all set’ for revision . The original version was partially revised in 1996, 2003 and 2007. Proposed date for release of draft guideline is October 2015.

The current annex 1 will be revised to facilitate implementation of the principles in the ICH guidelines and to extend the underlying concepts to include new areas of technology and processing not previously covered and also to clarify areas that have been highlighted as ambiguous due to the age of the document.

The revised guideline will clarify to what extent Q9 and Q10 should be followed in the design and implementation of facilities, equipment and processes for the manufacture of sterile medicinal products. Other changes that may require new GMP guidance include those for the revision to the Ph.Eur. monograph on methods other than distillation for the production of water for injection.

The current guideline does not reflect the advances in the manufacture of sterile medicinal products; the revised guideline will embrace the use of new technologies

to prevent detrimental impact on product and also to encourage the introduction of new technologies that are not currently covered. The current guideline contains historical inaccuracies and areas of ambiguity, the revised guideline will correct the inaccuracies and offer more detail to remove ambiguity and to give clearer interpretation of GMP expectations.

Proposed timetable

Preparation of draft concept paper - September 2014

Approval of draft concept paper - October 2014

Released for consultation – February 2015

Deadline for comments – March 2015

Discussion in PIC/S Committee – May 2015

Discussion in GMDP IWG - June 2015

Discussion with other Working Parties - June 2015 – September 2015

Proposed date for release of draft guideline - October 2015

Deadline for comments - April 2016

Re - discussion in GMDP IWG - June 2016

Re - discussion in PIC/S Committee – July 2016

Important facts to be remembered about 21 CFR

Important facts to be remembered about 21 CFR

·       The Code of Federal Regulations (CFR) is an annual codification of the general and permanent rules published in the Federal Register by the executive departments and agencies of the Federal Government. 

·       The purpose of the CFR is to present the official and complete text of agency regulations in one organized publication and to provide a comprehensive and convenient reference for all those who may need to know the text of general and permanent Federal regulations.

·       The CFR is divided into 50 titles representing broad areas subject to Federal regulation. 

·       Each Title is divided into chapters that are assigned to agencies issuing regulations pertaining to that broad subject area. Each chapter is divided into parts and each part is then divided into sections -- the basic unit of the CFR.

·       Title 21 of the CFR is reserved for rules of the Food and Drug Administration. Each title (or volume) of the CFR is revised once each calendar year. 

·       A revised Title 21 is issued on approximately April 1^st of each year and is usually available several months later.

·         21 CFR Chapter 1 divided into following sub chapters

• ·               SUBCHAPTER A — GENERAL (Parts 1 to 99)

• SUBCHAPTER B — FOOD FOR HUMAN CONSUMPTION (Parts 100 to 191)
• SUBCHAPTER C — DRUGS: GENERAL (Parts 200 to 299)
• SUBCHAPTER D — DRUGS FOR HUMAN USE (Parts 300 to 370)
• SUBCHAPTER E — ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS (Parts 500 to 590)
• SUBCHAPTER F — BIOLOGICS (Parts 600 to 680)
• SUBCHAPTER G — COSMETICS (Parts 700 to 741)
• SUBCHAPTER H — MEDICAL DEVICES (Parts 800 to 898)
• SUBCHAPTER I — MAMMOGRAPHY QUALITY STANDARDS ACT (Parts 900 to 900)
• SUBCHAPTER J — RADIOLOGICAL HEALTH (Parts 1000 to 1050)
• SUBCHAPTER K — TOBACCO PRODUCTS (Parts 1107 to 1141)
• SUBCHAPTER L — REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION (Parts 1210 to 1272)

    Subchapter C divided in to following Parts

• PART 200 — GENERAL ( 200.5 - 200.200)
• PART 201 — LABELING ( 201.1 - 201.327)
• PART 202 — PRESCRIPTION DRUG ADVERTISING    ( 202.1 - 202.1)
• PART 203 — PRESCRIPTION DRUG MARKETING        ( 203.1 - 203.70)
• PART 205 — GUIDELINES FOR STATE LICENSING OF WHOLESALE PRESCRIPTION DRUG DISTRIBUTORS (205.1 - 205.50)
• PART 206 — IMPRINTING OF SOLID ORAL DOSAGE FORM DRUG PRODUCTS FOR HUMAN USE ( 206.1 - 206.10)
• PART 207 — REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION ( 207.3 - 207.40)
• PART 208 — MEDICATION GUIDES FOR PRESCRIPTION DRUG PRODUCTS ( 208.1 - 208.26)
• PART 209 — REQUIREMENT FOR AUTHORIZED DISPENSERS AND PHARMACIES TO DISTRIBUTE A SIDE EFFECTS STATEMENT ( 209.1 - 209.11)
• PART 210 — CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL ( 210.1 - 210.3)
• PART 211 — CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS ( 211.1 - 211.208)
• PART 212 — CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION TOMOGRAPHY DRUGS ( 212.1 - 212.110)
• PART 216 — PHARMACY COMPOUNDING ( 216.23 - 216.24)
• PART 225 — CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICATED FEEDS (225.1 - 225.202)
• PART 226 — CURRENT GOOD MANUFACTURING PRACTICE FOR TYPE A MEDICATED ARTICLES (226.1 - 226.115)
• PART 250 — SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS (250.11 - 250.250)
• PART 290 — CONTROLLED DRUGS (290.1 - 290.10)
• PART 299 — DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES (299.3 - 299.5)

Part 210 - CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL Sections: 210.1 Status of current good manufacturing practice regulations. 210.2 Applicability of current good manufacturing practice regulations. 210.3 Definitions.

Part 211 -CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Subpart A--General Provisions    § 211.1 - Scope.    § 211.3 - Definitions. Subpart B--Organization and Personnel    § 211.22 - Responsibilities of quality control unit.    § 211.25 - Personnel qualifications.    § 211.28 - Personnel responsibilities.    § 211.34 - Consultants. Subpart C--Buildings and 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. Subpart 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. Subpart 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. Subpart F--Production and Process Controls    § 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. Subpart G--Packaging and 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. Subpart H--Holding and Distribution    § 211.142 - Warehousing procedures.    § 211.150 - Distribution procedures. Subpart 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. Subpart J--Records and 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. Subpart K--Returned and Salvaged Drug Products    § 211.204 - Returned drug products.    § 211.208 - Drug product salvaging.