Which GMPs Apply Since Most Phase I Drugs are Exempt from Full GMP Requirements, and What IND Data Requirements Are Necessary as a Result?

Which GMPs Apply Since Most Phase I Drugs are Exempt from Full GMP Requirements, and What IND Data Requirements Are Necessary as a Result?

An understanding of the GMPs that apply to Phase I drugs is necessary for professional in the clinical trials area for many reasons. With the FDA setting out rules under which most Phase I Drugs are exempt from full GMP requirements in 21 CFR Part 211 under 21 CFR 210.2(c), and with the subsequent IND data requirements; both applying GMPS when they are not required or not applying them when they are required result in considerable waste of resources and increase the chances of FDA actions.

Clinical Trials1

The operating guidance document set out by the FDA in this regard is the guidance document, “Good Manufacturing Practice for Phase I Investigational Drug Products”. This document relates to the correct GMP requirements that drug products made for the purpose of using an investigational drug product on human subjects for the first time should follow during conduct of Phase I clinical trials.

When does the FDA put the IND on clinical hold?

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If the FDA does not put an IND on clinical hold up to 30 days of receipt; it is assumed that the Phase I clinical trial can begin. The FDA puts an IND on clinical hold if it reviews an IND and finds that the information necessary and appropriate to give the FDA the confidence about the quality of the product is inadequate or unavailable. When the FDA puts an IND on clinical hold, the sponsor cannot go ahead with its clinical program. The criteria under which the FDA places an IND on clinical hold have been set out in its Guidance for Industry, the “INDs- Approaches to Complying with CGMP During Phase I”.

All the requirements for meeting the cGMPs with which clinical trial sponsors must comply have been set out by the FDA in its Final Rules of January 2006, which specified that most pharmaceutical products (including biologics) produced for use in Phase I clinical trial studies were exempted from complying with GMP requirements. Further, Section 501(a)(2)(B) of the FD&C Act mandates drugs, including IND products, to comply with cGMPs, and to be manufactured in compliance with cGMPs, failing which, they are deemed adulterated.

Get to understand the exemptions set out in 21 CFR Part 211

So, it is crucial for clinical trials sponsors to get a clear grasp of the requirements for an IND Phase I clinical trials, if they have to meet the FDA’s requirements. An in-depth understanding of this very important learning will be given at a two-day, in person seminar that is being organized by the highly reputable provider of professional trainings for all the areas of regulatory compliance, GlobalCompliancePanel.

21 CFR Part

The Director of this very valuable seminar is Stephanie Cooke, President and CEO of Cooke Consulting Inc. For about two decades, Stephanie has been providing global consulting services in various areas of Regulatory Affairs, Quality Assurance and validation for pharmaceutical, biological/biotech products, medical device, combination drug/device and nutraceutical firms.

She has extensive experience in the core areas of clinical trials, such as preparation of regulatory dossiers for human and animal pharmaceutical (chemical entities and biologically-based drugs), biotech products, drug/device combination products and medical devices in all stages of development (INDs, NDAs, BLAs, post-marketing supplements such as CBEs, Prior approval supplements, orphan drug designation and related submissions, 510ks, PMAs and HDEs).

Guidance which helps avoid unnecessary and repetitive batch productions

Stephanie will explain the specific GMPs for Phase I Investigational drugs, which will help them apply only those GMPs which are applicable to the drug product at this stage of development. This knowledge will help them avoid large, repetitive, commercial batch production and requirements, not to speak of the frustration and loss of resources this would entail.

Stephanie will also offer a complete understanding of all current Good Manufacturing Practices that are applicable to the manufacture of Phase I investigational drug product, in accordance with the FDA’s additional Guidance for Industry, “CGMP for Phase I Investigational Drugs”, which it issued in July 2008 with the purpose of providing guidance to sponsors regarding meeting GMPs appropriate for Phase I investigational drug products.

Drugs and Biologics Pharma Regulations

GMP requirements from the FDA

GMP requirements from the FDA

FDA Good Manufacturing Practices (GMP) is a set of guidelines issued by the FDA for various disciplines. There are GMP requirements FDA has for areas ranging from cosmetics to food to pharmaceuticals to API’s.

Why GMP’s?

Why are GMP requirements FDA has put in place necessary? It is for the simple reason that they are good manufacturing practices, and these practices have evolved over time. Being the regulatory body for the US; the FDA has to put a few practices into place, which will help manufacturers and consumers alike get the best out of a product.

Not the same as manufacturing process

It has to be understood that GMP’s are a set of guidelines, and are hence not to be confused with scientific literature or research that goes into a manufacturing process. GMP requirements FDA has are actually a product of many years of observation of the manufacturing process, whose implementation helps a product achieve its best results. GMP in itself is not a complete science, but a set of thumb rules that help manufacturers get the best out of their products.

Current good manufacturing practices

GMP requirements FDA has prescribed are collectively called by the term “current good manufacturing practices’, and are categorized under two headings:

  • Modernization of Food Good Manufacturing Practice Regulations
  • Dietary Supplement CGMPs

These are part of GMP requirements FDA has for the drug and food industries, which it regulates. These are contained in Title 21: Food and Drugs – PART 110—Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Human Food.





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History of FDA GMP requirements

History of FDA GMP requirements

The FDA has Good Manufacturing Practices (GMP) requirements for a range of items. One of them is Active Pharmaceutical Ingredients (API). FDA GMP requirements are established under the FDA Act. In Sec. 501 (a) (2) (B) of the Act (21U.S.C. 351(a) (2) (B)); the FDA seeks to establish API as a drug. It makes a drug subject to GMP. This is a culmination of a series of regulations on drugs and food that dates all the way to 1906, the year in which the Food and Drugs Act of 1906 was promulgated. A major landmark was the Food, Drug and Cosmetic Act of 1938.


Since they are important regulations, the finer aspects of GMP requirements need to be understood. Sec. 501 (a) (2) (B) of the FD & C Act requires that drugs be manufactured, processed, packed and held according to current good manufacturing practice (cGMP). GMP for API thus has a starting point in this legislation.

One of the important points relating to GMP is that FDA makes no distinction between API and finished pharmaceuticals, and failure of either to comply with cGMP constitutes a failure to comply with the requirements of the Act.

Historic guidances

Important regulations were passed in 1978 and 1998, and other guidances were established in PHRMA BPC Guidance, WHO Guidance and CEFIC Guidance. All of these were effectively replaced by the ICH Q7A of November 2000. It was accepted as an official guidance by the FDA the following year. Q9 Quality Risk Management was issued in 2006; Q10 Pharmaceutical Quality System was issued in April 2009, and the Q8 (R2) pharmaceutical development in November 2009. All these are essentially guidances on what a pharma company needs to do with regard to API.


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FDA API GMP requirements –current quality guidelines

FDA API GMP requirements –current quality guidelines

The US FDA has set out Good Manufacturing Practices (GMP) requirements for a number of products. The Food, Drug and Cosmetic Act, a US law,empowers the FDA with authority to regulate a number of industries.

Accordingly, the FDA GMP requirements and guidelines exist for a clutch of products and fields. GMP’s for some of these, concerning related areas like drug products, API, excipients, devices and nutritional supplements, may appear to be linked and similar, but they are not. Their definitions, identity, application and requirements may have many common qualities, but each has unique FDA GMP requirements.

Current quality guidelines for API

There are a number of current quality guidelines for FDA GMP requirements. A few of these are:


ICH Q 7 was issued as ICH Q 7A in November 2000. It was officially accepted by the FDA as a guideline for API in August 2001.

Q 8 (R2)

Concerning pharmaceutical development, Q 8 (R2) is another of the current FDA GMP requirements. It was issued in November ’09. It has applications to GMP’s.

Q 9

The Q9, concerning Quality Risk Management, was issued in June ’06.

Q 10

The Q 10, specific to the Pharmaceutical Quality System, was issued in April ’09.

Other guidelines concerning PV for APIs

The FDA also has draft guidances for process validation. These are:

  • General Principles and Practices (November 2008)
  • Pharmaceutical Components at Risk for Melamine Contaminations(August 2009)
  • Guidance for Industry –cGMP for Phase I Investigational Drugs (June ’08)
  • CPG Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval
  • 7356.002F –Active Pharmaceutical Ingredients are other important documents.

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Phone: 800-447-9407
Fax: 302-288-6884

1000 N West Street | Suite 1200 | Wilmington | DE | USA | 19801