Which SOPs are required by GMP?

ECA 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.

GMP News: Which SOPs are required by GMP?

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.



About Authors: 
Krunal Parikh1*, Mr. Maheshkumar Kataria2, Jatin Patel1
2Assistant professor, Department of pharmaceutics,
1Seth G.L. Bihani S.D. College of Technical Education,
Institute of Pharmaceutical Sciences and Drug Research,
Sri Ganganagar, Rajasthan, INDIA

Documentation is an integral part of good manufacturing practices. It defines a system of information and control so that risks so inherent in misinterpretation and/or error in oral communication are minimized. It consequently strengthens the quality, and its consistency, of all goods and services, as those responsible for the specific operations have clear, unambiguous instructions to follow including active drug substances, is legally mandatory.

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We are providing here details regarding how to write a standard operating procedure SOP for a WHO GMP Pharmaceutical Manufacturing unit. I am giving here a example SOP which will give you a exact idea ,so that you can write SOP of your company your self. I am keeping an example of a microbiology department for this purpose.


SOP No001
Page 2 of 4
Version: 1.4

Date: 02/09/20011

Revise by: 02/09/2014
Written by:M  S DHONI
Revised by : MS DHONI
Authorised by:MS DHONI
This is a guide to the format & writing content for including in a Standard Operating Procedures prepared in Microbiology & Biotechnology Departments.
Use clear, simple, direct wording in short sentences
Write procedures as chronological sequences
Use ‘shall’ or ‘must’ for mandatory actions and ‘should’ for advisory actions
Procedures should reflect current practice
If any section is not applicable to the procedure, include “N/A” under the heading –DO NOT leave blank.The final SOP should consist, as far as possible, of one single electronic master file.
A Standard Operating Procedure begins with an Introduction and does not include a preamble.
1. Introduction: (what the intention of SOP )
This introduction part provides background information on the procedure given in the
SOP. This may include the reason for carrying out a certain task, a brief explanation of the
interactions or theory behind a particular procedure or tast or process, and when it may be appropriate to conduct the procedure described.
Eg: The introduction for a SOP on ‘Protein Electrophoresis’:
This SOP discusses the procedure and safety guidelines for electrophoresis of Proteins.
When an electric charge is applied to an agarose gel, Proteins migrates through the gel matrix at a rate inversely proportional to the log10 of the number of amino acids and (if it is a DNA then it is number Bases).and depending up on the moleculer structure ,Super-helical, nicked circular, and linear DNA migrate at different rates relative to each other, and the relative mobility varies depending on many factors. DNA is visualised by the addition of a dye that intercalates between the stacked base pairs of the DNA molecule. Upon exposure to light of a specific wavelength, DNA-dye complexes emit fluorescent or luminescent light. Traditionally ethidium bromide dye has been used to visualise DNA. However, ethidium bromide is a strong mutagen and is being replaced by new non-mutagenic dyes with similar properties. SYBR Safe, a non-toxic dye, should now be used in place of ethidium bromide in this laboratory.
2. Scope(where this SOP applied)

This section states the circumstances under which the SOP is applied. Mention should be made of the extent or limitations of the SOP. If applicable, refer to associated regulatory or legislative information related to the work area or procedure described in the SOP.
Eg 1: This procedure applies to all staff in the Department of Microbiology .and to any visitors working in the Department.
Eg 2: This SOP sets out procedures for the cleaning, disinfection and sterilization of instruments and equipment, and maintenance of associated environments in a research laboratory. It may be suitable for application to instruments and equipment use in a veterinary practice. It does not apply to items intended by the manufacturer for single use only, nor to items that may be contaminated with unconventional infective agents, eg. Creutzfeldt.
3. Safety
This section must include all warnings of safety risks associated with performing the
procedure. These include but are not restricted to:
· Any general precautions or issues that need to be taken into consideration.
· Chemical Hazards: obtaining and reading of any relevant MSDSs, general or special
storage conditions; licences and permits required.
· Physical Hazards: RSI issues, use of trolleys, carrying of materials/loads, etc.
· Radiation Hazards: monitoring, wearing of badges, details of shielding required.
· Biological hazards: use of Class II cabinets; aerosol production;
requirements as determined by who guidelines and expanded for OGTR certified and QAP accredited laboratories.
· Use of PPE and any extra items that are identified as needed for the procedure.
· Accidents and spills: clearly stated instructions as to the steps that need to be taken,
precautions required and the correct method of “mopping” up and
disposal. First-aid procedure if applicable. Reporting procedure to supervisor and/or
Department Safety Officer, using Incident Reports .
4. Licences and PermitsThis section details all permits and licences that must be obtained before the procedure is
carried out. All permits and licences must be valid. Conditions required to comply with the
permits and licences should be noted on the SOP.
Permits and Licences may include:
Quarantine Approved Premises Certifications,licence for work and certification for facility, Poisons Licence and Poisons Control Plan, Dangerous Goods notification, who guidelines , etc
5. Training and Competency
· List all training needs required for the SOP and pre-requisites (ie. training in other
procedures or items of equipment, knowledge of other SOPs) required for this procedure.
Eg 1: Subculture of Microorganisms (non-pathogenic): The trainee must have already mastered an understanding of and have been given instruction in the use of asceptic technique.
Eg 2: Use of Departmental FACS Machine: Users are required to be registered and must undergo training by the FACS Facility Manager to obtain registration.
· Records must be kept of the personnel trained against this procedure. State where training records are kept.
· The trainee must be assessed to determine if they are competent to perform the
procedure. Competency may be assessed by close observation of the trainee by an
approved trainer along with either a verbal exam or completion of a written assessment
by the trainee. The method by which competency is determined should be stated in this
section, eg. by observation, written quiz, oral examination, continuous record of correct
results, etc.
6. Risk Assessments
Risk assessments must be performed on any procedure that has an element of hazard.
These assessments must be carried out by a staff member that has been trained in Risk Management (courses run by Faculty EHS Officer). Risk assessments should be kept as part of a Work Group Risk Register. Any assessments associated with a SOP should be referenced in the Risk Assessments section of the SOP, and should be attached to a hardcopy of the SOP document. If the SOP is to be stored as an electronic file only, then the risk assessments should be attached as part of the electronic copy of the SOP.
7. Equipment and Maintenance / Handling and Storage / LabellingIdentify any special equipment used, describe location of equipment, location of instruction
manuals and any particular cleaning strategies. Service and maintenance details may also be
included here. Alternatively, use this place to describe the storage and handling of chemicals/ biologicals, etc. State any special handling and transport procedures.
Eg: Transporting a gel around department requires microbiological gel to be placed in a sealed container and one glove removed to avoid contaminating doors and lifts.
Give details of any specific labelling required. A template or picture of the label can be
8. Operating Procedures
The operating instructions or methodology must be written in a recipe-like manner – an
ordered list of clear, concise instructions or action steps.
If applicable include:
· Location where procedure will be done (eg. lab, bench, Biosafety cabinet, fume hood).
· Labelling requirements at the steps where the need arises.
· Troubleshooting information.
· Clear instructions on cleaning and/or decontaminating work area, equipment and other
materials used in the procedure.
· State any routine maintenance requirements.
9. Controls and Calibrations
Any internal or external quality control procedures or issues should be documented here.
Provide any calibrations required for specific items (pH meter, micropipettes). Routine steps
should also be included at the appropriate step in Section 8.
Waste DisposalState specific waste disposal procedures for all items in the SOP. Include type of waste
containers to be used and any special transport or labelling requirements.
11. Relevant Documents / ReferencesRelevant external documents and procedures may apply to the SOP. Examples: WHO Guidelines,website, manufacturer’s operating instructions, scientific literature.
List complete details of any external documents or websites relevant to or required for the
SOP. Risk assessments applicable to the SOP are listed in Section 6.
12. Signage / Summaries / TemplatesAny signs or summaries specifically relating to the SOP should be included here. This
includes simple step-by-step notices, warning signs, and templates for use in conjunction
with the SOP, eg. for recording data or carrying out audits. Include information such as the
number of copies of a sign or notice that needs to be printed, if these need to be laminated,
and where these need to be displayed in appropriate areas or on relevant equipment.
13. Appended MaterialIf the SOP is to be stored as a hardcopy with appended documents (which do not form part of
the electronic SOP file), then a detailed list of all appended material is to be recorded in this
section. This acts as a check in case this material is separated from the SOP, and aids in
assessing the complete SOP when revision is required.The entire SOP, including appended items, should be kept as one complete document.Document control details (ie. SOP number, version, date, etc) should be shown on all the pages of a SOP, including the pages which contain appended material.