cGMP: What Every Life Science Researcher Should Know About Current Good Manufacturing Practice
This article is posted on our Science Snippets Blog
An Interview With Ravid Grimberg, Head of RA Advanced Therapies & Cell Culture Media, Regulatory Compliance, Sartorius
Can you tell us about yourself?
After finishing my bachelor’s degree in Biology and my master’s degree in Quality Assurance and Reliability from The Technion-Israel Institute of Technology, I gained experience by working in different positions in QA and RA within the pharma, cosmetic, and medical device sectors. I started working at BI (now part of sartorius) because the field of cell therapy fascinates me and it gives me great fulfillment to be part of such a ground-breaking area. Working closely together with our customers, who are often in the development stage of designing new cell therapies, gives me great satisfaction. We accompany those customers through in their processes with full understanding and implementation of the various regulatory aspects’ requirements and implementation and needs. Our customers seek consultation in this field and I feel proud to be able to offer them this added value.
What is GMP?
GMP stands for Good Manufacturing Practice, which is a set of regulations, rules, and guidelines published by all healthcare authorities. Examples of these healthcare authorities include:
- US Food and Drug Administration (FDA)
- World Health Organization (WHO)
- European Union (in the EUDRALEX)
- UK Medicines & Healthcare Regulatory Agency (MHRA)
GMP regulations provide us with a system that should ensure consistent, controlled products and services. Good implementation of the regulation requirements/guidelines helps us provide the best and safest services and products for our customers. These GMP guidelines include all aspects of the product’s life cycle and manufacturing process, from product development and raw materials selection to the final production process, testing, storage, and shipment.
GMP is also referred to as “cGMP”. The “c” stands for “current” as a reminder that systems, processes and technologies must be kept up to date to comply with the latest regulations. Sartorius follows all cGMP-applicable regulations, which help us minimize and even eliminate all risks of contamination, incidents, and mistakes.
How did the idea of GMP begin?
The history of GMP is fascinating. The need for regulation originated out of tragedy and corruption, from the days when horse urine was labelled and sold as medicine. In 1937, glycol was used as an ingredient in cough syrup, resulting in the death of over 100 children and adults. Because of this horrifying case, the Food, Drug & Cosmetic (FD&C) Act was established in 1938, followed by the writing of GMP rules and regulations ultimately to protect the public health. You can learn more about this event from the FDA.gov website here.
Is Sartorius's cell culture media facility in Beit Haemek GMP and are your products GMP?
Yes, the facility is GMP , and more accurately, it is cGMP-compliant. This is a good question since there is much confusion regarding the term GMP. It sounds strange, but there is actually no such thing as a “GMP facility”. However, there are products and facilities that meet the GMP requirements. The more appropriate term is cGMP. Our products are manufactured under a strict quality management system based on these cGMP regulations.
Sartorius’s media for cell therapy are considered “ancillary materials”, meaning they are materials that come into contact with cells that will ultimately become a medical product or be part of a medical product. Our goal is to minimize any risk associated with these products by complying with cGMP regulations, so not to endanger the final medical product. Here GMP steps in; the methodology of cGMP is based on risk-analysis, and its purpose is to identify any potential hazards and reduce them to a minimum.
Can customers receive a GMP certification?
It is important to understand that the FDA does not “approve” or certify health care facilities, laboratories, or manufacturers as GMP. The FDA inspects product manufacturers to verify that they comply with good manufacturing practices but does not issue GMP certificates. Therefore, a GMP certificate for a facility or laboratory does not exist. A GMP certificate can only be obtained for products that are considered a drug or an Active Pharmaceutical Ingredient (API). There are some companies in our sector that claim to have a GMP certificate, but this certificate is associated with a specific pharmaceutical product, drug, or API, and not the company itself.
Nevertheless, we implement all applicable cGMP guidelines within our facility in order to provide safe and valid ancillary products and in vitro diagnostic (IVD) products of the highest quality. An important note is that, according to the FDA, the ISO 13485-certified quality management system meets all FDA GMP requirements. We have held the ISO 13485 certification since 2006, have been ISO 9001-certified since 1995, and we undergo a successful inspection every year.
How do you and your team keep up to date with the latest GMP requirements?
Since Sartorius’s facility is registered with the FDA, we automatically receive regulation updates directly from the FDA. For other countries, we need to initiate active updating of requirements ourselves. Therefore, our regulatory department uses the services of international consultants, and we attend many courses and seminars to keep updated regarding any new and changing requirements.
Our customers are subject to the requirements of pharmaceutical cGMP and require us to meet the demands of changing regulations. To ensure we are up to date with our practices, they perform quality audits at our manufacturing facility and communicate with us through quality agreements, which reflect the current GMP requirements. In some cases, we find ourselves to be on the consulting side to our customers and even to the authorities. Our regulatory department has increased significantly as we dedicate even more resources to our growing cell therapy product portfolio, and we can offer our customers the highest level of quality available today. We truly take pride in our knowledge and standards of regulation to meet our customers’ needs.
Has Sartorius’s site in Israel been audited by the FDA?
The FDA usually does not perform audits at facilities that produce ancillary products, and therefore we have not gone through an FDA audit – but we will be more than happy to do so if asked. When we submit a Drug Master File to the FDA, and when our customers apply for an Investigational New Drug (IND) through the FDA that includes a Sartorius product, we are open to an FDA audit at any time. We have passed many audits by other regulatory entities, such as the European Notified Bodies.
Personally, I consider audits by our customers to be the most important test for us. Our customer’s feedback is very important to us. We routinely pass our customers’ audits without any special remarks or non-conformances, and for me it is a pleasure to see what we and the customer learn from each audit, and how we apply these experiences toward further improvement.
What does it mean if a product is labelled as “GMP Grade”, ”Research Grade” or “IVD Grade”?
The term “GMP Grade” is a marketing term used for products produced under cGMP requirements. This term does not reflect a products’ intended use, or the listing or official registration status of a product. “Research Grade” is a term used for products that have no specific definition and cannot be registered at any official body.
For IVD reagents, it is important to understand that In Vitro Diagnostic (IVD) materials can also be considered medical devices, meaning that IVD is a classification and not a “grade”. IVD-classified products are intended for the use in the collection, preparation, or examination of specimens taken from the human body.
Most of our products are classified as IVD, and they are produced under applicable cGMP guidelines, EC/98/79 directive, and sterile products standards (ISO 13408, ISO 14644). We can ensure and declare that we follow the latest requirements, and that we implement these requirements in order to provide our customers the best quality and safety.
Can Sartorius media products be used in clinical trials?
Yes, the cell therapy media are defined as ancillary products or are IVD-classified (depending on the product), and can be used according to their designation, including in clinical trials. Ancillary materials are products that are part of the cellular therapy process but are not part of the final product. Our products come into contact with the cell or tissue product during the production of cells for therapy but are not intended to be part of the final product formulation. Though they may not be part of the end treatment, we understand that ancillary products are an important part of the overall process.
In order to better meet the needs of research moving toward clinical trials, we have moved away from relying on animal sources, such as serum, that contain undefined and unknown components – and potentially even viruses – which can endanger the final product. Because of the potential hazards inherent with animal-derived reagents, we are focused on developing complete, defined, xeno-free, and serum-free products that consist of recombinant proteins and chemicals with known formulation and low risk. Over the years, our company has proven to be a pioneer in the field of xeno-free and serum-free product development.
What is a Drug Master File and why is it important?
A Drug Master File is a file submitted voluntarily to the FDA that contains detailed information about the ingredients, manufacturing facility, manufacturing processes, and any other processes or procedures involved in the production of a specific product.
A DMF is an extremely strong safety net for our customers and has two very important benefits. First, when working with a company that has filed a DMF, you know that this company is being transparent and obligated to perform its processes in the correct manner. It is a company that is confident, willing to receive criticism, and is not afraid to expose itself to audits by the FDA. The second important benefit comes when a customer wants to register a new product with the FDA through an investigational new drug (IND) application. This registration process is significantly shortened when using raw materials, tools and processes of manufacturers that have filed a DMF for these specific materials.
A DMF must be submitted according to a specific format and must meet certain requirements put in place by the FDA. Currently our company has filed three DMFs which are acknowledged by the FDA for NutriStem® hPSC Medium, for the complete MSC NutriStem® Medium and for NutriFreez® D10 Cryopreservation Medium. DMFs for other products, such as 4Cell® Nutri-T GMP Media and NutriFreez® D5 Salt-Based Cryopreservation Solution, are being registered now, with anticipated approval by Q2 2022. . We worked closely together with the FDA to file these DMFs.
Is NutriStem® hPSC Medium and MSC NutriStem® Medium the only xeno-free, serum-free stem cell media with a DMF registered with the FDA?
To the best of our knowledge, we are the only company that has a DMF for specific xeno-free, serum-free stem cell media which contains complete information. Compared to using media with a less specific or incomplete DMF, this uniqueness can dramatically shorten the time of receiving FDA approval when a new product or IND application is filed with the FDA.
Is a DMF country-specific, or is it only valid in the US?
Sartorius's DMFs are submitted directly to the US FDA. Any customer applying for an investigational new drug (IND) through the FDA can incorporate and reference the information within our DMF to accelerate the process of the application. In order to convey this information, the customer must send a request for a Letter of Authorization (LOA) to Sartorius. Sartorius will send this LOA to the FDA’s Centre for Biologics Evaluation and Research (CBER) or the centre for Drug Evaluation and Research (CDER), giving the FDA permission to incorporate our DMF information with the IND application.
For customers that wish to apply to other regulatory authorities worldwide, we have created a detailed dossier for this purpose, which contains most of the information included in the DMF. If the regulatory authority needs any additional information, we are willing to send it directly to them.