Good Manufacturing Practices (GMP) are a set of product quality regulations that have the force of law and require that manufacturers and packagers of medicines and medical devices take steps to make sure their products are safe, pure and effective.

GMPs cover all aspects of production, from raw materials, factory and equipment, manufacturing, personal hygiene, training, packaging and labeling, record keeping, personnel, product testing, and addressing errors and complaints.

GMPs are the law of the land and failure to comply can result in severe consequences including product recall, seizure, fines, and in extreme cases, even jail time.

In this article, we are going to dig deep into GMPs and answer many of the misconceptions and misunderstandings about the use and application of GMPs on the factory floor.

BTW, if you want to get a solid understanding of GMP rules, regulations and guidelines, check out our 6-Week GMP Training For Beginners in the Pharmaceutical Industry.

1. What are some things a GMP Manufacturing must do?
2. Why are GMPs Important?
3. What are the Different Types of GMPs?
4. The Regulatory Authorities
5. Cross Recognition of Regulation
6. Licences and Authorisations
7. People can’t be GMP certified. Nor can companies
8. Regulatory Inspections
9. What is the difference between GMP and cGMP?
10. What are GxPs?
11. What is a Quality Management System and how does it fit together with GMPs?
12. How does ISO 9001 compare with GMPs?
13. Do all the ingredients and materials that go into a finished drug product need to be manufactured under the control of GMPs?
14. How do I get started using GMPs within a manufacturing plant?
15. 18 rules of working on the factory floor in a GMP Manufacturing plant
16. The 12 Principles of GMP
    • Rule #1 Get the factory design right from the start
    • Rule #2 Validate the design and processes
    • Rule #3 Write good standard operating procedures (SOPs)
    • Rule #4 Identify who does what
    • Rule #5 Ensure SOPs and work instructions are being followed
    • Rule #6 Keep good documentation and records
    • Rule #7 Maintain facilities and equipment and storage
    • Rule #8 Prevent contamination through cleanliness
    • Rule #9 Train and develop staff
    • Rule #10 Build quality into the entire production process
    • Rule #11 Use quality risk management tools
    • Rule #12 Perform regular quality audits

Good Manufacturing Practices establish minimum standards for the manufacturers of pharmaceutical and medical device products. Each manufacturing plant must:

• set up a robust quality management system
• have detailed written procedures for each process that could affect the quality of the finished product
• obtain appropriate quality raw materials
• establish operating procedures for consistently manufacturing safe medicines and medical devices
• detect and investigate product quality deviations
• maintain reliable testing laboratories
• have a well-documented system to provide evidence that the employees are following the correct procedures at each step in the manufacturing process every time a product is made

The end result is that GMPs help make sure the patients get the right product at the right strength and that it is:

• free from contamination
• is correctly labeled
• is sealed and protected against damage or tampering
• is stored correctly

GMP regulations also help minimize or eliminate instances of contamination, mixups, and errors and protect the patient from purchasing a product that is not effective, dangerous or even deadly.

A key tenet of GMPs is that testing alone is not adequate to ensure quality, as quality cannot be tested into a product. Rather quality must be built into the process of everything from the development of the product to its manufacturing, to its distribution and storage, all the way until it is used by the patient.

For the most part, GMP requirements are general rather than specific, as every product and process are unique, and can be improved upon over time.

This allows each manufacturer to decide the best way to implement the necessary controls within the guidelines outlined in the regulations. It also allows companies to interpret the GMP regulations in a patient-centric manner which makes sense for each business.

Medicines change the way that the body functions and so the public expects that they are safe, effective (that is that they work) and consistently manufactured to the right quality.

With most other manufactured products if something is wrong with the item, then the end user may spot the problem before they take or use the product.

This is not the case with medicines. It’s almost impossible for a medical professional, much less a patient to know through looking at or touching or smelling a tablet or an injection if it is safe to use before taking it.

This risk is further compounded as when we take medicines and inject them directly into our bloodstream, we bypass the many defence mechanisms our bodies have for protecting us against harm, and so leaving us terribly exposed to the slightest manufacturing error or impurity within that medication.

And so, the public, patients and the medical profession need to be confident that:

• the manufacturer produced the medicine to a high level of precision and safety and has taken every step to ensure this is the case.
• no shortcuts have been taken in the manufacturing process or the sourcing of ingredients that could affect the strength, quality and purity of the final products

The United States, European Union, Japan, China, India, Korea, the UK, World Health Organisation (WHO), etc all have their versions of GMPs. There are other standards that aim to harmonise GMP requirements across countries and promote cross-recognition of standards across different regulatory jurisdictions such as the ICH (International Conference on Harmonisation) the PIC/S (Pharmaceutical Inspection Co-operation Scheme) organisation.

Many countries will often use one of the above sets of regulations rather than go to the expense of developing their own. The particular regulation the manufacturer will be subject to depends not only on the location of the manufacturing plant but especially on the location of the market the medicine or medical device will be supplied for patients. But the ultimate goal of GMPs is always to prevent harm to the end-user.

In addition, each country has an organisation or agency that is responsible for the safety and efficacy (i.e it works) of the drugs that are manufactured and sold within its jurisdiction. The regulatory authorities will grant a license to a manufacturing plant to make a product based on that facility’s adherence to the relevant GMP regulations and enforce GMP regulations.

The regulatory authority may create its own GMP regulations and enforce them on any manufacturing plant supplying medicines to the public within its jurisdiction. For example, in the United States, the FDA (Food and Drug Administration) enforces its own 21 CFR Part 211 GMP regulations. The European Union has the EMA (European Medicines Association) which works together with the local regulatory authorities in each of its 27 member states who regulate their local manufacturers using the EU’s Eudralex regulations).

Even though the United Kingdom has left the EU, GMP regulations are still harmonized across Europe and UK manufacturers of medicines continue to work to the EU’s Eudralex regulations.

In addition, it’s common for a regulatory agency to audit and inspect a plant located outside its jurisdiction if that plant’s products are going to be supplied to the public within its jurisdiction. For example, there are a number of plants in Ireland, India and China which are inspected and audited by FDA inspectors as the products manufactured in those plants are going to be sold within the USA.

In the not to distance past, it was not uncommon for a single manufacturing plant that was supplying product to different markets in Japan, Korea, the EU, USA, Canada etc, to be audited by the regulatory authorities from every single one of those countries. The plant would find itself in a state of being constantly audited. Needless to say, this was incredibly expensive and wasteful so to reduce the regulatory cost and burden, the regulatory agencies have been developing mutual cross-recognition agreements. So for example, if a plant in Japan is authorised by the PMDA (Pharmaceuticals and Medical Devices Agency), other regulatory agencies will recognise that authorisation removing the need for them to go an audit that factory and vice versa.

Once a new medicine has successfully completed its clinical trials, the relevant regulatory authority will grant it a “Marketing Authorisation or Product Licence”. This means that the medicine is approved for use.

In addition, the manufacturing plant where the medication is going to be made must have and maintain a “Manufacturing Authorisation” or “Manufacturing Licence”. To obtain this authorisation or licence or regulatory authorities must audit and approve the pharmaceutical plant where the medication is made.

Perhaps an often misunderstood point from people outside the industry is that technically speaking the pharmaceutical or medical device manufacturing company is not approved to make a specific medicine or product at all of its manufacturing plants. Instead, the regulatory authorities approve a specific product to be manufactured at a specific manufacturing plant. In other words, the local regulators (MHRA, FDA, etc) have visited, inspected and audited that facility and certified it to manufacture that product conditional on demonstrating strong regulatory commitment and compliance to the relevant GMP standards.

GMPs focus on the outcomes of the facility as a whole and not on the actions of one individual who was involved in its production. So the people or even the company aren’t certified. Only the manufacturing facility is certified to manufacture a specific product.

However, you may sometimes hear people say that a product is GMP Certified especially if they are from North America. What this means is that the product was made in a GMP-approved facility.

The regulatory authorities conduct routine and surprise inspections of sites that manufacture medicines making sure these are working to the principles of GMP and are in compliance. They check whether the manufacturing plants have the necessary facilities, equipment, and ability to manufacture the drug it intends to market.

If a company fails to comply with GMP regulations, it can result in severe consequences including, restriction, suspension or forfeiture of rights to continue manufacturing the goods, product recall, seizure of the goods, fines, and even jail time.

These inspections are typically conducted every two or three years and if the inspections do not go well, the site could be put under warning or even closed. More frequent inspections will occur if the authorities have any concerns.

cGMP stands for “Current Good Manufacturing Practices”. The Food and Drug Administration (FDA) in the USA wanted to remind drug manufacturers of the need for continuous improvement in their approach to product quality.

The FDA warned against a “set and forget” approach to compliance with the GMP guidelines, and wanted manufacturers to make sure that product quality became a core focus within their organisations. Systems and equipment used to make products that may have been outstanding 20 years ago may be far from adequate by current standards.

Most countries don’t use the ‘c’ for ‘current’ as it’s assumed that manufacturers will keep up to date with changes to the GMP guidelines and will strive to meet them. And so for most practical purposes the terms cGMP and GMP are largely interchangeable terms.

Lifecycle overview showing where GxP and GMP is implemented.

A quality management system documents a company’s processes, procedures, and responsibilities to help it provide a quality product or service. It helps coordinate and direct an organisation’s activities to meet customer and regulatory requirements.

Arguably the most recognised and widely implemented quality management system is the ISO 9001 standard. This standard is published by the ISO organisation based in Switzerland and provides a set of requirements for an organisation regardless of what it does or its size. It’s a tried and tested framework for managing the organisation’s processes so that they consistently turn out products that satisfy customers’ expectations.

A company that uses ISO 9001 can have itself audited by the ISO organisation and publicly state that it is “ISO 9001 Certified” or “ISO 9001 Registered”. However, certification to the ISO 9001 standard does not guarantee compliance with GMPs (and therefore the quality) of end products and services. Rather, it certifies that consistent business processes are being applied. That is all.

While GMP regulations and ISO standards are often compared, the two are not the same and are not really trying to do the same thing.

Think of GMPs as regulations and legal requirements that pharmaceutical manufacturers must comply with. Think of the implementation of a quality management system such as ISO 9001 as a framework you can use to achieve compliance with those regulations and legal requirements

GMP is a product quality regulation that has the force of law behind it. Its focus is on getting product efficacy, (i.e it works) and manufactured to a high-quality standard for the most important customer of GMPs – the patient. If your manufacturing facility doesn’t strictly follow GMPs, the local regulatory authority can compel the plant to make changes, recall products, or even halt production.

ISO 9001 is a tried and tested quality management system that is regularly used by pharmaceutical manufacturers to help meet its GMP regulatory requirements. ISO 9001 is also more about running the whole business, a goal of which will be producing products of the right quality – but it has other aims too. Whilst GMP focuses on regulating production and quality control – ISO 9001 focuses on all departments and processes of an organisation.

Yes. However, the GMPs for excipient fillers in a tablet, are different to the GMPs for the APIs (Active Pharmaceutical Ingredients) in the same tablet, which are different to the GMPs for active ingredients in an injectable.

These in turn are different to Water for Injection (WFI) which is added to the same injectable, which are different to the GMPs for the blister pack materials or vials in which they are packaged for distribution to the patients, which are different to the GMP’s governing the product instructions for the patient who will be taking the medicine that are included in the packaging box.

There is a vast difference in the level of understanding you need of GMPs depending on whether you work in the factory floor vs working in a quality assurance role or managment position. And so if you look at good manufacturing practices from various regulatory authorities from around the world, you could condense the principles into two perspectives.

The Tactical level rules and guidelines for those working directly on the factory floor.

Lets take a look…

Imagine you have to write a list of rules and guidelines for everybody who works within the manufacturing area in a GMP-regulated facility. What would they be?
Here is a list of rules and good practices when working on the factory floor:

1. Make sure you’re using the correct procedure when performing any task.
2. Always try to follow the standard operating procedure as tightly as possible.
3. Accurately record information when you perform a task.
4. Only perform tasks that you are trained and competent to do.
5. Always report any mistakes and problems that occur.
6. Work in a clean and tidy manner to reduce the chances of mistakes.
7. Always check that you’re using the correct equipment and materials.
8. Only go into areas you’re permitted to.
9. Try to minimise your physical movement with the GMP-controlled area.
10. Make sure you gown up properly wearing the correct clothing.
11. Always use a pen when making an entry on a paper record.
12. If you make a mistake, cross the error out with a single line so that the original can still be read and sign and date the error.
13. Never eat or drink inside a GMP-controlled area.
14. Never take shortcuts no matter how sensible they seem as it may lead to unintended consequences that you have not foreseen. Always follow instructions.
15. Make sure equipment, materials and areas are clearly labelled and identified
16. Work logically and in a manner that avoids mix-ups with the wrong materials
17. Work to prevent contamination of one material and another
18. If you’re ever not sure, ask for help.

High-level principles for those working in the quality department and management that you can use to drive day-to-day operations.

Let’s take an in depth look…

If you were to look at the various GMP regulations from around the world, you could condense them into the following list of 12 items for the quality department and management. If fact, many of these principles would equally apply in any manufacturing industry, but they specifically apply to the biomedical manufacturing industries.

1. Get the factory design right from the start
2. Validate the system
3. Write good standard operating procedures (SOPs)
4. Identify who does what
5. Enforce / Implement SOPs and work instructions
6. Keep good documentation and records
7. Maintaining facilities and equipment
8. Prevent contamination through cleanliness
9. Train and develop staff
10. Build quality into the who product lifecycle
11. Use quality risk management tools
12. Perform regular audits

Pharmaceutical and medical device manufacturers have to follow GMP regulations when manufacturing product. However, it’s going to be much easier to be GMP compliant if you get the  design and construction of the facilities and equipment right from the start. For that reason, you should front-load your efforts on building quality processes into your design so that you can avoid production and quality problems from the start rather than trying to procedularise out the problems when the plant is up and running. As the saying goes, an ounce of prevention is worth a pound of cure as having to make changes to the plant once it’s up and running is going to be prohibitively expensive. 

Gruman Aircraft Corporation (the maker of the Apollo lunar landing module) followed a simple rule of thumb when designing new aircraft in that, you can choose a new engine, a new airframe or a new avionics system but never more than one new system at the same time. With that in mind, here are a few simple design corollaries.

• Use of the shelf-proven parts.
• Minimise the part count.
• Leverage in-house expertise and outside supplier expertise. Try to maximise the use of seasoned engineering and science expertise as this can save a world of problems.
• Use risk assessment analysis of the design to try and visualise catastrophe before it happens. 

Factory Layout

Lay out the production area to reduce the chances of cross-contamination and to avoid mix-ups and errors. For example, don’t have the final product passing through or near areas that contain intermediate products or raw materials.  

• remove unnecessary traffic in the production area to minimise the chance of contamination
• segregate materials, products, and their components to minimise confusion and the potential for mix-ups and errors. 

Design:

What you are making is going to determine a lot of the building and facility requirements. You may need to conduct a risk assessment analysis to identify the right materials and design features. 

• Materials of Construction – Stainless steel piping, tanks, floor, wall, ceiling covering, etc
• Windows
• HVAC requirements
• Utilities
• Emergency power
• Access to site

Environment  

You must control the air, water, lighting, ventilation, temperature, and humidity within a plant so that it does not impact product quality. 

Make sure that:  

• the facility has good lighting.
• temperature, humidity and ventilation are controlled
• interior surfaces (walls, floors and ceilings) are smooth, free from cracks and do not shed particulate matter  
• interior surfaces are easy to clean  
• pipework, light fittings, and ventilation points are easy to clean  
• drains are sized adequately and have trapped gullies.  

Equipment

The equipment should be:

• suitable for its intended use  
• clearly labelled. 
• easy to repair and maintain
• properly installed and calibrated at regular intervals   
• designed and installed in an area where it can be easily cleaned 

Validation is a legal and regulatory requirement for the manufacture of medicines. You have to prove that equipment and processes consistently do what they are supposed to do before you start production. 

So what is validation?

Pharmaceutical Validation creates a documented evidence trail (through rigorously checking and testing) to demonstrate that a system, procedure or process used in the production and testing of the pharmaceutical product:

• maintains compliance at all stages
• and leads to a consistent and reproducible result

There are many other definitions of validation but the essence of all these definitions seems to be “documented scientific proof of consistent performance“.

Pharmaceutical validation can be divided into two broad elements.

1. Equipment Qualification
2. Process Validation
3. Cleaning Validation
4. Computer System Validation (CSV)

Equipment Qualification

Equipment Qualification (sometimes referred to as IQ OQ PQ) ensures that equipment operates as intended and is installed i