FDA & EU Requirements for Documentation & Approval of GMP Procedures


FDA documentation requirements

FDA Requirements for Signatures & Documentation

What does the FDA require for the documentation, signature, and approval of standard operating procedures (SOPs)? Are the requirements the same for Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP)? As it turns out, the answer is no. FDA has different regulatory requirements for GCP, GMP, and GLP regulations. In this Guest Commentary Kathie Clark describes the FDA and EU requirements for documentation and approval of GMP procedures. And understanding the basics of good documentation helps in any area of FDA regulated industry.

Guest Commentary:

Approval & Signature Requirements for GMP Documents, by Kathie Clark

Complete, accurate and clear documentation is key to maintaining compliance in a Good Manufacturing Practices (GMP) environment. Documentation is needed to define quality management principles, describe specific procedures, and maintain records that demonstrate that procedures were followed. Together, these directives, procedures and records demonstrate that a manufacturer is operating in a state of control, defined as “A condition in which the set of controls consistently provides assurance of continued process performance and product quality” .
GMPs specifically require that “The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.” But what does this mean in terms of required signatures?

Some people may be surprised to find that the US GMPs only require signature (or initials) for a handful of documents. The following are the specific GMP signature requirements:

FDA documentation GMP signature

What Procedures are Required?

§ 211.182 Equipment cleaning and use log. The persons performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under § 211.68, just the person verifying the cleaning and maintenance done by the automated equipment) shall date and sign or initial the log indicating that the work was performed.

§ 211.186(a) Master production and control records. …master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person.

§ 211.186(b)(8) Master production and control records. A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling.

§ 211.194(a) Laboratory records. The initials or signature of the person who performs each test and the date(s) the tests were performed. The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

§211.188(a) Batch production and control records. An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed

documentation and signatures for FDA requirements

Review and Approval Process for GMPs

What’s the impact? Although some documents require signature according to regulations (CFR) in the US, a closer read indicates that the real emphasis is on defining and following a sound review and approval process, and being able to provide evidence of this, for all documents. There is no indication that you are out of compliance if an SOP or specification does not display handwritten or electronic signatures, as long as a valid process was followed for the document.

In Europe, GMPs would initially seem to set the bar higher as they state that “Documents containing instructions should be approved, signed and dated by appropriate and authorised persons.” However, a closer look at recent revisions made to EudraLex, The Rules Governing Medicinal Products in the European Union Volume 4, to support electronic signatures for GMP indicates that electronic signature requirements in Europe (for GMP documents) are less stringent that in the US:

Electronic records may be signed electronically. Electronic signatures are expected to:

a. have the same impact as hand-written signatures within the boundaries of the company,
b. be permanently linked to their respective record,
c. include the time and date that they were applied.

documentation and approval for FDA

Documentation for
Review, Approval,
& Release

Since there is no explicit requirement for the signature to appear in the document, this could be interpreted as an electronic approval recorded in a document management system. In summary, recommendations based on a review of the guidance include:

• Ensuring that the process to review, approve and release any GMP document is clearly defined in writing and followed consistently.
• Reviewing the signature requirements in the region in which you operate and determine the most efficient way to meet them.
• If you are not already using an electronic system to manage your documentation, considering the return on investment you may be able to achieve from cost reductions in the “Four Ps” of paper, printing, postage, and processing. If you must print, courier and archive paper documents to comply with the regulations, the cost can be significant.

Kathie Clark is Director, Product Management at NextDocs Corporation, where she is responsible for NextDocs’ Quality Management and Regulatory SharePoint-based document management solutions.

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READ THE GMP DOCUMENTS:

PHARMACEUTICAL QUALITY SYSTEM Q10, International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use, 4 June 2008

21 CFR 212.22 Responsibilities of quality control unit

EudraLex The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Chapter 4: Documentation, Revision January 2011

EudraLex The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 11: Computerised Systems, Revision January 2011

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On the Blogroll: The AssurX Blog recently posted this interesting article about FDA Inspections

Barry A. Friedman discusses FDA Warning Letters for APIs in China and clinical trial materials in the U.S..

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FDA EU documentation

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4 Responses to FDA & EU Requirements for Documentation & Approval of GMP Procedures

  1. GxP Perspectives says:

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  2. Craig says:

    I am wondering if, while explicit in the regs, the FDA makes a distinction between “approval” and “signature”. That is, is the FDA accepting of approval documentation that does not contain a signature (obviously not where the regs explicitly state that a signature is required)?

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