Which SOPs are required by GMP?

Recommendation

4/5 December 2024
Berlin, Germany

Root Cause Analysis
A CAPA Workshop on Successful Failure Investigation

The ECA Academy is receiving a lot of questions on SOPs (Standard Operating Procedures) needed in a GMP environment. The most interesting is the one on which SOPs are required by law. Here is an Overview:

U.S. Food and Drug Administration (FDA):

A three year old Notice focusing on specific recordkeeping requirements in the Federal Register also gives a very good summary of SOPs required by 21 CFR Part 211:

"Written procedures (standard operating procedures - SOPs), are required for many Part 211 records. The current SOP requirements were initially provided in a final rule published in the Federal Register of September 29, 1978 (43 FR 45014), and are now an integral and familiar part of the drug manufacturing process."

The 25 SOPs provisions under Part 211 include:

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.

European Union:

SOPs required by EU-GMP are mainly defined in the EU Guidelines to Good Manufacturing Practice of Eudralex Vol. 4 (EU-GMP Guide). There is no comprehensive list provided but Chapter 4 of Part 1 (Documentation) of the Guide gives some examples:

"There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples:

Validation and qualification of processes, equipment and systems;
Equipment assembly and calibration;
Technology transfer;
Maintenance, cleaning and sanitation;
Personnel matters including signature lists, training in GMP and technical matters, clothing and hygiene and verification of the effectiveness of training.
Environmental monitoring;
Pest control;
Complaints;
Recalls;
Returns;
Change control;
Investigations into deviations and non-conformances;
Internal quality/GMP compliance audits;
Summaries of records where appropriate (e.g. product quality review);
Supplier audits."

Chapter 4.30 requires that operating procedures "should be available for major items of manufacturing and test equipment."

World Health Organisation (WHO)

A very comprehensive list can be found in the WHO guide to good manufacturing practice (GMP) requirements, Part 1: Standard operating procedures and master formulae. Although written as part of the Global Programme for Vaccines and Immunization, Vaccine Supply and Quality, this overview gives valuable guidance also for other pharmaceutical companies.

More than 75 SOPs are listed from the following areas in Appendix 1 ("List of Document Requirements"):

Raw Materials
Biological Starting Materials
Facility
Equipment (Production and QC)
Production
Labelling and Packaging
Quality Control
Quality Assurance

The examples from FDA, EU and WHO provided above are not a finite list. Some topics might be split in a number of SOPs for the sake of practicality. Some other company or quality system specific processes might be defined in SOPs as well.