What is good manufacturing practice (GMP)?
Good Manufacturing Practice (GMP) – are a set of product quality regulations that have the force of law and require that manufacturers and packagers of both medicines and medical devices take steps to make sure their products are safe, pure and effective.
GMPs establish minimum standards for the manufacturer’s of these products. They 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.
GMPs cover all aspects of production, from raw materials, factory and equipment used for manufacturing, the manufacturing process itself, personal hygiene, training, packaging and labelling, recordkeeping, personnel, product testing, and addressing errors and complaints.
Each manufacturing plant must set up a robust quality management system, obtain appropriate quality raw materials, establish operating procedures for consistently manufacturing safe medicines and medical devices, detect and investigate product quality deviations, and maintain reliable testing laboratories. The manufacturing plant must have detailed written procedures for each process that could affect the quality of the finished product. There must be 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 processes must be reliable and produce the consistent results every time within acceptable bands of variation.
The end result is that GMPs help make sure the patients get the right product at the right strength, that is free from contamination, is correctly labelled, is sealed and protected against damage or tampering and is stored correctly. GMP regulations also help minimise or eliminate instances of contamination, mixups, and errors and protect the patient from purchasing a product which is not effective, dangerous or even deadly.
A key tenant 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 development of the product, to its manufacturing, to its distribution and storage, all the way until it is used by the patient. GMPs are the documented and regulated systems that ensure this is consistently done every time.
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 to make medicines and medical devices more affordable to patients, and therefore available to more people. This allows each manufacturer to decide the best way to implement the necessary controls within the tram tracks outlined in the regulations. It also allows companies to interpret the GMPregulations in a patient-centric manner which makes sense for each business.
Why are GMPs Important?
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.
Quality is important for many industries, however only some products are life critical and if something is wrong with them then the end-user cannot take them back to the shop and replace them with a working model.
This is 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, thereby bypassing the many defence mechanisms our body’s 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
Different Types of GMPs
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.
The Regulatory Authorities
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 licence 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.
Cross Recognition of Regulation
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.
Licences and Authorisations
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.
People can’t be GMP certified. Nor can companies
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.
What is the difference between GMP and cGMP?
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.
What are GxPs?
GxPs is an umbrella term for several “Good Practice” regulatory frameworks which includes “GMPs”. These frameworks were created to make sure that high levels of quality and safety are built into every step from drug development and manufacture to distribution and storage as we don’t just want only the manufacturing process to be safe. We need these other steps and processes to be safe as well.
Drug discovery: Good Laboratory Practice (GLP)
Drug trials: Good Clinical Practice (GCP)
Manufacturer: Good Manufacturing Practice (GMP)
Distribution: Good Distribution Practice (GDP)
Storage: Good Storage Practice (GSP)
And collectively, all these standards are known as GxPs.
Lifecycle overview showing where GxP and GMP is implemented.
What is a Quality Management System and how does it fit together with GMPs?
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 “ISO9001 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.
How does ISO 9001 compare with GMPs?
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.
Do all the ingredients and materials that go into a finished drug product need to be manufactured under the control of GMPs?
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.
However, all the GMPs share the common basis of meeting the rules governing the manufacturing of safe medicines for patients, the guidelines as to how these rules are applied by the FDA auditors, and the risk management tools used to make scientific-based decisions to prevent problems from happening in the first place and to correct them with a Patient Safety mindset when deviations occur.
How do I get started using GMPs within a manufacturing plant?
If you look at good manufacturing practices from various regulatory authorities from around the world, you could condense the principles into:
Tactical level rules and guidelines for those working directly on the factory floor
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 a look at both perspectives.
18 rules of working on the factory floor in a GMP Manufacturing plant
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:
Make sure you’re using the correct procedure when performing any task.
Always try to follow the standard operating procedure as tightly as possible.
Accurately record information when you perform a task.
Only perform tasks that you are trained and competent to do.
Always report any mistakes and problems that occur.
Work in a clean and tidy manner to reduce the chances of mistakes.
Always check that you’re using the correct equipment and materials.
Only go into areas you’re permitted to.
Try to minimise your physical movement with the GMP-controlled area.
Make sure you gown up properly wearing the correct clothing.
Always use a pen when making an entry on a paper record.
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.
Never eat or drink inside a GMP-controlled area.
Never take shortcuts no matter how sensible they seem as it may lead to unintended consequences that you have not foreseen. Always follow instructions.
Make sure equipment, materials and areas are clearly labelled and identified
Work logically and in a manner that avoids mix-ups with the wrong materials
Work to prevent contamination of one material and another
If you’re ever not sure, ask for help.
The 12 Principles of GMP
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.
Get the factory design right from the start
Validate the system
Write good standard operating procedures (SOPs)
Identify who does what
Enforce / Implement SOPs and work instructions
Keep good documentation and records
Maintaining facilities and equipment
Prevent contamination through cleanliness
Train and develop staff
Build quality into the who product lifecycle
Use quality risk management tools
Perform regular audits
Rule #1 Get the factory design right from the start
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.
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.
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
Access to site
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.
The equipment should be:
suitable for its intended use
easy to repair and maintain
properly installed and calibrated at regular intervals
designed and installed in an area where it can be easily cleaned
Rule #2 Validate the design and processes
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.
Equipment Validation or Qualification
Equipment Validation or Qualification ensures that equipment operates as intended and is installed in accordance with the manufactures recommendation. New facilities and equipment, as well as significant changes to existing systems, all require equipment validation.
Equipment Validation is split into several qualification stages. Here are the different qualification stages using a piece of equipment as an example.
A User Requirement Specification (URS) states exactly what you want. For example, what you expect an item of equipment to actually do.
Design Qualification (DQ) covers how the item will be designed, such as its materials of construction and operational capabilities.
Installation Qualification (IQ) checks that you’ve got what you wanted and that the item has been installed correctly.
Operational Qualification (OQ) checks that each individual function of the item performs as expected, such as, it runs at the required speed.
Performance Qualification (PQ) we make several batches, at least three, and test them extensively to show that the item is consistently capable of making a product of the right quality.
Process Validation involves gathering documented evidence to confirm a particular process performs consistently and meets predetermined specifications.
Ensure all validation activities are well planned and clearly defined and documented in a Validation Master Plan, or VMP.
Put a change control system in place to document all changes to facilities, equipment, or processes that could affect product quality. You must assess all changes to see if they have an impact on product quality and the whole quality management system.
And, after the installation and validation of any change, conduct an evaluation to confirm that there were no unintended negative impacts on product quality. So there needs to be a system to review changes before they take place. There also needs to be a review after the change has been implemented not only to check that the change has worked but there’s been no negative effect elsewhere as a result of the change.
Rule #3 Write good standard operating procedures (SOPs)
Written procedures provide detailed step-by-step instructions for the operators and users. They promote consistency and reduce variability as they allow the same task to be performed in the same way by different people. They also act as a reference. If a change or an improvement is identified, having a procedure in place creates a clear starting point which can be improved upon or modified in a controlled manner.
Writing Good Procedures
Written procedures are only effective if they are followed correctly, consistently and at all times by everyone.
Make a quick outline of the task before you start writing the procedure.
Use clear and precise language. Try to visualise the person that will use them. Use language they will understand.
Steps should be numbered clearly and individually to make them easy to follow. Remember that people don’t usually read procedures from start to finish; they tend to scan the document for keywords. You can reduce this tendency by numbering each step.
Break the procedure into chunks. Use heading, tables, bullet points and diagrams where necessary as this makes the information easier to digest and follow.
Use simple sentences and write in a conversational style.
Rule #4 Identify who does what
Individual responsibility should be clearly understood and defined in job descriptions and everyone should have an up-to-date training record. All employees should clearly understand what they have to do each day as it avoids misunderstandings and minimises the risk to product quality.
You should create a job description for each role to define:
duties and responsibilities
There should be no gaps or overlaps in responsibilities.
Create an organisational chart and display it on the intranet or a local notice board. This way everyone in the organisation can see who does what.
Rule #5 Ensure SOPs and work instructions are being followed
It’s all very well to have great written procedures in place but we also have to have documented evidence that we actually follow them consistently as it’s a GMP requirement.
It often happens that the steps described in a written procedure may not seem most efficient way of performing the task. Taking shortcuts may save time or make the task easier, but you should never deviate from a written procedure without the approval of a supervisor or the Quality Department.
There are two main reasons for this:
Many shortcuts can lead to unintended consequences that you have not foreseen.
Each step in a procedure has been included for a purpose.
The inclusion of a particular step may not be obvious to you but it may be there as a check for another stage of the process. Of course, we should always strive to improve the process and eliminate waste but don’t change procedures without assessing the impact on the entire process.
Rule #6 Keep good documentation and records
It is an essential part of GMP to keep accurate records. This not only covers the rules for paper-based documents and records but also computer-based systems too. Good records enable you to track all activities performed during manufacture from the receipt of raw materials, to the final product release and allows for an investigation in case anything goes wrong. Good documentation control helps convey that you are following procedures to any auditor and demonstrates that processes are known and under control.
Follow these guidelines to ensure that good record keeping is part of your everyday culture:
Records must be completed at the time of action and paper-based records must be completed using a pen.
Record all necessary information immediately upon completion of a task. Never trust your memory or write results on loose pieces of paper.
Write your name legibly in ink. Remember that by signing records you are certifying that the record is correct and that you have performed the task as per the defined procedure.
Corrections to entries in records should be crossed out with a single line (to allow you to read the original entry) and be signed and dated. Correction fluid cannot be used. Include a reason for the correction at the bottom of the page.
Record details if you deviate from a procedure. Ask your supervisor or the Quality Department for advice should a deviation occur.
Don’t document someone else’s work unless you are designated and trained to do so.
Never assume that undocumented work has been properly completed – if it’s not written down then it didn’t happen!
Rule #7 Maintain facilities and equipment and storage
Regular maintenance prevents equipment breakdowns which could disrupt production and can be very costly so it’s crucial to set up and preventive maintenance plan to make sure the facilities and equipment remain in good working order and fit for use. And.
All equipment should be routinely maintained and calibrated where necessary.
You should have written procedures for both scheduled and emergency maintenance. These should outline who does the work, the tasks involved and any additional information required.
It’s a GMP requirement to have a maintenance schedule in place with the frequency determined by the criticality of the equipment.
Storage areas should be kept clean and dry and free from pests. You need to provide suitable and secure premises and equipment that keeps materials and product within the correct storage conditions so that it does not get damaged, deteriorates or is tampered with.
Premises should be of adequate capacity and have suitable lighting so the task can be performed accurately and safely. The environment should also be monitored, especially the temperature. Deviations from set points must be acted on and documented.
Materials and products should be stored in a manner that prevents mix-ups of different batches and materials.
Rule #8 Prevent contamination through cleanliness
Practice good hygiene
It’s critical to reduce the risk of product contamination to a minimum by putting a program in place to maintain the cleanliness of the cleanroom. Develop a program to meet the standards of cleanliness necessary for the product. As an example, you would have different cleaning standards for sterile products used in an operating theatre as opposed to products that you inject into your bloodstream.
Keep these practices in mind:
Always practice good personal hygiene by washing your hands at regular intervals
Wear the required PPE protective garments and follow the gowning procedures.
Inform your manager if you are ill
Minimise contact with product or product contact surfaces and manufacturing equipment
Never eat, drink, smoke or chew in manufacturing areas.
Always follow cleaning and sanitation procedures.
Report any condition that may cause product contamination.
Remove rubbish and waste materials, and store them appropriately.
Rule #9 Train and develop staff
GMP has a big focus on the training of all people who have an impact on product quality. It’s crucial that your staff know how to do their job right first time, every time.
You should provide training for all employees whose duties take them into production areas or laboratories, and whose activities could affect the quality of the product. The training should cover how staff are expected to deal with problems, deviations, investigations, and changes. You should also provide training in response to the installation of new equipment or negative trends and inspection findings, as well as any new regulatory requirements.
Job-specific training is normally done by departmental trainers but QA has a role in training as well. This usually involves making sure that all staff are trained in good manufacturing practice and the quality system itself.
Rule #10 Build quality into the entire production process.
As previously mentioned, a key tenant of GMPs is that you can’t test your way into high-quality productions. Rather, you must build quality into the entire manufacturing system during all stages of the manufacturing process. But what does that mean and how does building quality into the entire manufacturing system reflect itself on the factory floor?
What that means is that you must establish effective controls across the entire production process to assure product quality.
Facilities must be clean, tidy and dry. Be of sufficient space to avoid mix-ups, with all equipment and rooms identified as to what is currently occurring. Steps should always be taken to avoid cross-contamination of one material and another.
Warehouse and Storage
In the warehouse, materials must be checked on arrival to ensure that they are what was ordered in the first place, are in the right condition, are labelled correctly and have been transported correctly. Any problems must be reported and problem items segregated from good stock. Materials cannot be used until approved by Quality Control.
The temperature of the warehouse must be recorded and deviations from established limits reported. If items need to be held under refrigerated conditions, then they need to be moved to the correct storage location on arrival.
All materials must be labelled with their name, batch number, as well as the expiry date and status such as “on test” or “passed”.
At all stages during manufacture, the equipment and rooms used should be identified with the product name and batch number. Steps must be taken to avoid cross-contamination of one item and another. So, use the required ventilation equipment, keep doors closed, only open one container at a time, clean up any powder or spills and clean up when you’ve finished the job.
At all times, wear the appropriate protective clothing correctly. Follow the instructions exactly for any job recording what you do at the time. If any problems occur, if you make a mistake, if anything does not look right, or anything out of the ordinary occurs, then report this to your supervisor straight away.
Packaging and Labelling Controls
With packaging, the use of the wrong materials can result in the end-user being given an incorrectly labelled medicine and this can be fatal. Great care is therefore needed to ensure that you have the correct materials and the work area is completely free from the previous batch before the packaging operation starts.
A packaging line must be set up exactly as instructed. During packaging, in-process control checks check that the pack is satisfactory with materials separated and inspected if there is a problem. There needs to be good segregation between different activities to avoid mix-ups and at the end of the job, the line and area, are thoroughly cleared of finished material and unused stock.
Rule #11 Use quality risk management tools
In manufacturing, testing, and distributing pharmaceutical or medical device products as in life, there are a lot of risks. With QRM, we make extensive use of worst-case scenario planning to figure out what could go wrong and come up with steps to mitigate those risks.
Think of it as a way of visualizing catastrophe before it happens and coming up with preventive steps either by designing out the problem (preferred) or procedurilize-out the problem (last resort).
So it is essential to do risk assessments if you want to change something or when something has gone wrong. Things to consider when doing a risk assessment following a problem include:
● The risk to product quality, safety and efficacy
● The risk to the end-user
● The risk to the process, area or equipment
● The risk to other batches, as well as
● The risk to your own personnel who do the job such as health and safety risks
Rule #12 Perform regular quality audits
And finally, we need to make sure that we’re doing what we’re told to do in a quality management system and that we are following our procedures.
You have to ensure that our facilities are fit for purpose, that we are validating our work, that our people are trained, that the plant is clean and we are controlling the process parameters in order to yield a particular product of a certain quality.
You should also conduct in-house audits, or self-inspections, to ensure GMP compliance.
See the checklist below. It’s a good practice to undertake a self-audit a few times a year and to target different manufacturing areas and departments each time.
Are all staff properly trained to perform the functions and activities of their roles? Is training linked to the relevant SOP(s) for that employee?
Does each employee have a training record showing scheduled and completed training? Is it directly accessible by that employee, indicating the date and the type of training?
Do you assess and document the competency of employees regularly?
Does each employee receive retraining on an SOP if operationally significant changes have been made to the procedure?
Are training records readily retrievable to ascertain and prove what training an employee has received, which employees have been trained on a particular procedure, or have attended a particular training program?
Are all your GMP trainers properly qualified through experience and training?
Do you have an accurate organisational chart?
Do you have a dedicated quality function/department within the business?
Does the quality department have the authority and responsibility to approve or reject all components, drug product containers, in-process materials, packaging materials, labelling and drug products?
Does QA have a person or department specifically responsible for designing, revising, and obtaining approval for production and testing procedures, forms, and records?
Can employees quickly and easily report quality events (issues, incidents, concerns and near misses) to the quality department, should they wish to do so?
Are your consultants, contractors, suppliers, vendors and other third parties properly certified, trained and approved for that function?
Are written records maintained stating the name, address, qualifications and date of service for any consultants and the type of service they provide?
Do you have a central listing of all live Standard Operating Procedures (SOPs)?
Are Standard Operating Procedures (SOPs)? available in their appropriate locations?
Do you have an overarching SOP governing how other SOPs are drafted, revised, distributed, controlled and archived?
Is there an SOP review schedule to make they remain up-to-date, compliant and fit for purpose?
Are all QA procedures and responsibilities fully documented, current and approved?
Is there a formal auditing function in the quality assurance department?
Does your facility have current written procedures for acceptance/rejections of products, containers, closures, labelling and packaging materials?
Is each lot within each shipment of material or components assigned a distinctive code so material or component can be traced through manufacturing and distribution?
Are all materials handled in such a way as to prevent contamination and to allow for cleaning and inspection?
Are the production batch record and release test results reviewed for accuracy and completeness before a batch/lot of finished product is released?
Are complaints, whether received in oral or written form, documented in writing and retained in a designated file or electronic database?
Are complaints reviewed on a timely basis by your quality control unit, with documentation of any actions taken (or consciously not taken)?
Is a documented and approved quality policy made available to all employees?
Have you put a change control system in place to control and amendments
Are deviations from standard procedures fully documented?
Does the QA department routinely review production records to ensure that procedures are followed and properly documented?
Do you have documented specifications for raw materials, components and the finished product?
Are standard methods followed for manufacture, packing, testing, sampling, status control, stability testing and records?
Do you have a mechanism in place for reporting and acting on quality events such as batch management, product deviations, change requests and so on?
If you’re a medical device organization, do you have a standard documented product design control methodology combining and comprising user requirements, inputs, outputs, risks and change controls? (Note: design controls are not explicitly connected to good manufacturing practice (GMP) requirements, but the same principles of complete and thorough process documentation apply.)
Can you trace the end-to-end development history of the products your customers receive from you, from manufacturing to distribution?
Are all product information, documentation and tasks, such as trace matrices, product requirements and approvals, standardised across your business even if taking place within separate computerized systems?
Has each supplier/vendor of material or component products to your organization been inspected/audited for proper manufacturing controls according to a documented procedure?
If your business accepts products from a supplier, is at least one test conducted to confirm the identity of raw material (bulk chemical or pharmaceutical) when a Certificate of Analysis is provided by your supplier and accepted by QA, with additional testing if no certificate is provided?
Are labels for different products, strengths, dosage forms, etc., stored separately with suitable identification?
Are rejected components, materials, and containers quarantined and clearly marked to prevent their use?
Are inventory control procedures written?
Does your product control program identify destruction dates for obsolete or outdated materials, components, and packaging materials, with destruction activities fully documented and timestamped?
Is stock rotated to ensure that the oldest approved product or material is used first?
Premise and Equipment
Is your office, warehouse, manufacturing site and general working facility clean and properly maintained?
Are all parts of the facility constructed in a way that makes them suitable for the manufacture, testing, and holding of your products, including available space, ventilation, lighting, air and water control?
Do you have operational environmental controls and a facility safety program, and are they regularly audited?
Do all staff have access to the correct safety equipment and PPE required for their role, with training completed before working in the premises?
Do you have documented cleaning, sanitation, cross-contamination prevention and waste disposal SOPs?
Are adequate space, equipment and qualified personnel available for required testing?
Do you have a properly maintained space for equipment, assets and paper-based documents?
Is all equipment used to manufacture, process or hold your product of appropriate design and size for its intended use?
Are machine surfaces that contact materials or finished goods non-reactive, non-absorptive, and non-additive so as not to affect the product?
Are written procedures available for each piece of equipment used in the manufacturing, processing or holding of components, in-process material or finished product?
Are all pieces of equipment clearly identified with easily visible markings?
Do you have a documented process for validating and qualifying the equipment your organisation uses?
Have you made a centralised equipment and asset inventory, including instruction and operation manuals?
Do you have a documented process for replacing equipment or assets whose health falls outside the agreed tolerance limits?
Are there documented and visible calibration and maintenance schedules?
Does each maintenance and calibration event have an accompanying log capturing the time, date and relevant personnel?
Are the records of equipment/asset calibration and maintenance securely stored and traceable?