The article covers the requirement of written procedures required by 21 CFR 211. As with the similar blog articles on documents required by EU GMP and ISO 9001 the reader should note that the words “written procedure” are not the same as “procedure”. The word “procedure” is mentioned many times in GMP, but strictly speaking an activity only needs to be formalised into a controlled document if the words “written procedure” exists.

Here are the 25 times that a written procedure is required by 21CFR211 (1978 version). Apologies if I have missed any.

Section 211.22(d)-Responsibilities and procedures of the quality control unit;
Section 211.56(b)-Sanitation procedures
Section 211.56(c)-Use of suitable rodenticides, insecticides, fungicides, sanitizing agents;
Section 211.67(b)-Cleaning and maintenance of equipment;
Section 211.68(a)-Proper performance of automatic, mechanical, and electronic equipment;
Section 211.80(a)-Receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers or closures;
Section 211.94(d)-Standards or specifications, methods of testing, and methods of cleaning, sterilizing, and processing to remove pyrogenic properties for drug product containers and closures;
Section 211.100(a)-Production and process control;
Section 211.110(a)-Sampling and testing of in-process materials and drug products;
Section 211.113(a)-Prevention of objectionable microorganisms in drug products not required to be sterile;
Section 211.113(b)-Prevention of microbiological contamination of drug products purporting to be sterile, including validation of any sterilization process;
Section 211.115(a)-System for reprocessing batches that do not conform to standards or specifications, to insure that reprocessed batches conform with all established standards, specifications, and characteristics;
Section 211.122(a)-Receipt, identification, storage, handling, sampling, examination and/or testing of labeling and packaging materials;
Section 211.125(f)-Control procedures for the issuance of labeling;
Section 211.130-Packaging and label operations, prevention of mixup and cross contamination, identification and handling of filed drug product containers that are set aside and held in unlabeled condition, and identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch;
Section 211.142-Warehousing;
Section 211.150-Distribution of drug products;
Section 211.160-Laboratory controls;
Section 211.165(c)-Testing and release for distribution;
Section 211.166(a)-Stability testing;
Section 211.167-Special testing requirements;
Section 211.180(f)-Notification of responsible officials of investigations, recalls, reports of inspectional observations, and any regulatory actions relating to good manufacturing practice;
Section 211.198(a)-Written and oral complaint procedures, including quality involving specifications failures, and serious and unexpected adverse drug experiences;
Section 211.204-Holding, testing, and reprocessing of returned drug products; and
Section 211.208-Drug product salvaging.

Please feel free to comment.

THIS ARTICLE WAS FIRST PUBLISHED IN 2012. IT HAS BEEN REVIEWED AND UPDATED IN DECEMBER 2022.

Annex 1 has finally arrived, 25th Aug 2022 saw the publication of Annex 1. Normally, updates to GMP chapters and Annexes have a 6-month lead time for implementation. In the case of the new Annex 1, the lead time is 12 months, except for clause 8.123 relating to lyophilization which has 24 months lead time.

Annex 1 was first issued in 1971 as the only annex in the first ever UK guide to Good Manufacturing Practice. Since then, there have been several updates but not full revisions. In 2012 there was a proposal to revise Annex 1 with a re-proposal in 2014 by the UK’s MHRA. At the time, a full rewrite was considered unlikely and instead the intention was to provide a document that would confirm regulatory expectation and as such, not place any new requirements or costs on the pharmaceutical industry.

While this principle, is still upheld, it was clear from the first draft for public comment of December 2017, that a rewrite was being undertaken. The first draft created around 6200 comments coming from regulatory organizations, such as the pharmaceutical cooperation scheme, regulatory bodies outside of the EU, support organizations such as the Parenteral Drug Association, the Parenteral and Healthcare Sciences Society, the Pharmaceutical Microbiology Interest group as well as representatives from the manufacturers within the pharmaceutical industry to name just a few. Rarely do updates require a second public consultation but in the case of the annex 1 update a second draft was issued in March 2020 although this was a more targeted review in terms of the sections and clauses that comment was being sought for.

About the author

Andy Martin

Andy started working in the Pharmaceutical industry in 1985 as a lab technician for Smith & Nephew. Following this he had a number of roles culminating when he took over as QA Microbiology Manager. In 2003 he moved into Pharmaceutical Training and then in 2007 he moved back into Microbiology when he took up the position of Microbiology Manager for Catalent Pharma Solutions. Since 2012 he has operated as a consultant specialising in Microbiology and Quality Systems.

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3 Comments

Vilma Villalta on March 9, 2012 at 6:29 pm
Where costly fines and severe “punishment” are at stakes, due to failure to comply with regulations, it is not surprising that certain keywords are spelled and emphasized repeatedly. This is something that some mathematicians or physicists find burdensome or even redundant but it makes sense.
Dr. Bulcsu Herenyi on March 12, 2012 at 12:24 pm
Written procedures are not enough. They must be in operation. If you have written procedures but they do not work, during an inspection it will be a finding. You have to prove also in written reports that your procedures are in operation.
Anupsinh Gadhavi on March 31, 2023 at 6:58 am
Now a days written procedures are available from various sources like web, Consultant, etc…important thing is all the written procedures should be in accordance to your in-house operations and there is no any mismatches.