In-Process Adsorbents in the US and European Pharmaceutical Industries

Introduction

As the network of companies that make products for the pharmaceutical industry continues to grow, the suppliers that support them and the regulatory agencies that oversee them are forced to evolve. Quality regulations, that ensure pharmaceutical products are safe and effective, are a key component of the medicinal industries.¹ Because pharmaceutical procurement departments are often the first to do business with companies outside their regulated industry, they are frequently tasked with having to bridge the communication between their own industry and suppliers outside of it. Some regulatory areas are not always well understood and it is good to have, on both sides of the pharmaceutical company/supplier equation, an understanding of how regulations influence the decisions pharmaceutical companies make.

All U.S. Food and Drug Administration (FDA) registered ingredients, whether active or inactive, are listed in the United States Pharmacopeia and the National Formulary (USP-NF), which details the FDA’s expectations for purity, potency and efficacy for drug products.² Although the USP-NF addresses expectations for drug products, the current Good Manufacturing Practices (cGMP) laid out in Code of Federal Regulations 21 (21 CFR) are where the FDA’s expectations for manufacturing and quality systems in a drug product facility can be found. Between the USP-NF, and regulations set out in 21 CFR, regulatory oversight, by the FDA, for active ingredients and excipients is fairly clear. For materials that are not ingredients, on the other hand, the FDA does not require them to be listed in the USPNF or for the manufacturers of those products to use cGMP during production. Materials that are not considered ingredients lie within a regulatory area that isn’t clearly defined, from a quality standpoint, and how to handle those materials in a cGMP facility can be left open to interpretation. Because the quality guidelines are not as clearly outlined for non-ingredient materials, a buyer can find themselves asking: Which grade should I be procuring? In-process adsorbents like silica gels, activated aluminas and activated carbons are examples of such materials, with non-ingredient applications, and are often used in pharmaceutical manufacturing facilities as desiccants, in chromatography, and in batch extractions. Non-ingredient adsorbents can be mistakenly presumed as ingredients, because of their chemical nature, and because some adsorbents do have dual applications as ingredients. To better grasp the level of regulatory oversight for noningredient adsorbents in the pharmaceutical industry, it is a good idea to first look at where the US and EU regulatory agencies get their authority and the scope of their reach.

cGMP Regulations

According to 21 CFR, §210.1, cGMP are:³

“methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess.”

In the US, 21 CFR 210 and 211 specifically outline the cGMP for drug products and pharmaceuticals that are required by the FDA.⁴ In addition to providing guidelines and regulatory expectations for how pharmaceutical facilities operate, the term cGMP itself, when used to define a grade of material, can also serve a purpose. Besides defining manufacturing expectations by regulatory authorities, cGMP represent multiple things to the customers buying products that are advertised with that designation. If a product is made in in the US, in a cGMP facility, it tells a customer that the manufacturing facility is regulated by the FDA and the products being legally sold by that facility have not been adulterated (made in a way that compromises their purity, compromises their potency or results in mislabeling or misbranding).⁵ For US pharmaceutical companies, cGMP grade signifies that a material should match the specifications, and other requirements related to packaging, storage and labeling, as set out in the USP-NF monograph. Monographs detail what quality requirements are expected by the FDA, EMA and the companies buying the products and they can also list what tests are used to confirm the identity of such materials.

US Code Title 21 grants the Health and Human Services (HHS) department jurisdiction over Food and Drugs, and the Federal Food, Drug, and Cosmetic Act (Chapter 9 of US Code Title 21) establishes the legal framework within which the FDA operates. If an adulterated drug product is being sold by a company, the legal recourse the FDA can take is outlined in US Code Title 21 (which can range from seizure of the product, an injunction or even prosecution). The U.S. Federal Food, Drug, and Cosmetics Act also designates the USP-NF as the official compendia for drug products marketed in the United States.⁶ The European Union has a similar system with the EMA, the EudraLex (rules governing medicinal products in the European Union) and the European Pharmacopoeia (or Ph. Eur.).⁷

Since 1990, the drive to harmonize the development, registration and production of safe, effective and high quality medicines has been funneled through an organization called the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).⁸ ICH brings together regulatory authorities from around the world, including representatives from the US and EU, to discuss the challenges being faced in pharmaceutical manufacturing environments and to provide guidelines to the world’s regulators with the aim of harmonizing pharmaceutical lifecycles worldwide.⁹

Although the guidelines set forth by the ICH are often referenced by the FDA and EMA, guidelines such as ICH Q7 “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients”, ICH Q9 “Quality Risk Management” and ICH Q10 “Pharmaceutical Quality System” are merely guidelines. The individual regulatory agencies are responsible for implementation of any guidance set forth by the ICH.

If there is any uncertainty about whether or not a chemical product needs FDA or EMA oversight, the best place to look for making that determination is the USP-NF or Ph. Eur. Although there are new active pharmaceutical ingredients and excipients being discovered all the time, a part of the registration process for a new drug is submitting a New Drug Application (NDA) to the FDA and/or EMA, which details everything from the in-process materials used to make the drug, to its manufacturing processes, and ensures the eventual inclusion of any newly discovered ingredients in the USP-NF and/or the Ph. Eur.10 If a material is listed in an official pharmaceutical compendia, a manufacturer needs to then determine if the product they are selling is intended for use as a drug or as an ingredient in a drug.

The USP-NF only lists monographs for drug substances, dietary supplements, ingredients and excipients (adsorbents do not fall into those categories when used as desiccants, in chromatography or in batch extractions). There is a reagents section in the USP-NF, which is meant to detail guidelines for mixtures or substances used for chemical analysis of drug and drug ingredients and, for some of the reagents listed, the guidelines provided are simply to use suitable or ACS grade material; while other reagents may reference a USP monograph (neither section, ingredients or reagents, applies to noningredient adsorbent applications in production).

In-Process Adsorbents

Non-ingredient adsorbents can be best described as in-process materials and in-process materials, according to 21 CFR §210.3, are:¹¹

“any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product”

Often, in-process materials are not manufactured under cGMP conditions and are not regulated by the FDA or EMA. What can be misleading, is that some adsorbents, like silica gel (silicon dioxide), activated alumina (aluminum oxide) and activated carbon, are used in a variety of applications and do have monographs listed in the USP-NF. ¹² In the end, it is up to the pharmaceutical customer whether they want to use a cGMP grade product or not, but using a cGMP grade chemical as an in-process adsorbent can, not only be unnecessarily costly, it can make finding a supplier very difficult. Just because a material is listed in the USP-NF, it does not mean it is frequently used as an ingredient. For many in-process adsorbents a cGMP grade is difficult to find because it doesn’t currently exist (usually because there is no demand for that type of material from other drug product manufacturers).

During inspections of cGMP facilities, regulatory agencies use a stepby-step approach to identify possible sources of manufacturing nonconformances.¹³ If a non-conformance is identified, auditors might look at what indicators are used by a cGMP manufacturer to bring attention to process problems, the degree of risk posed by specific failures, how familiar a cGMP manufacturer is with a process and how well validated a process is. For example, if the FDA notices, during an inspection, that there have been repeated bioburden failures for a stainless steel product transfer line, they might look at what indicators are used to determine that the line is clean, if the transfer line is used at an upstream or downstream point in the manufacturing process (to assess potential risk) and how well validated the procedures associated with the transfer line are. Note that all of the previously mentioned activities involve the cGMP manufacturer not the supplier of the steel piping or the contractors that welded the pipes together. You could compare a chromatographic adsorbent to the stainless steel product transfer piping (as the oversite they receive from auditors should be similar). For example, let's say the FDA finds a non-conformance in a production purification process that uses chromatography. The auditors might look at what indicators are used by the cGMP manufacturer to assess incoming quality of the chromatographic adsorbent, where the purification is in the production process and how well the cGMP manufacturer validated the purification process (responsibilities of the non-conformance again residing with the cGMP manufacturer).

There are other non-cGMP grade materials, besides adsorbents and stainless steel piping, which can be found in pharmaceutical manufacturing facilities. In the modern era of pharmaceutical manufacturing, even active pharmaceutical ingredients can be manufactured in a non-cGMP facility (one that isn’t regulated by the FDA). Non-cGMP active ingredients, even though they have a monograph listed in the USP-NF and/or Ph. Eur., are often referred to as intermediates if the manufacturer is not registered with the FDA or EMA (the products they make may not meet the purity, safety and efficacy standards as determined by either regulatory agency). A cGMP facility may buy a non-cGMP intermediate and then purify it, or reprocess it, to a point where it meets or exceeds the specifications detailed in its monograph so it can then be included in a drug product.¹⁴ The process of buying an intermediate and then further processing it is usually reserved for ingredients. Although cGMP manufacturers may wash in-process adsorbents to remove fines or condition the material prior to use in production, the adsorbents pose a much lower level of risk than an active ingredient because they are not a component of the final drug product.

In-process materials like adsorbents, although they are made at un-regulated facilities, are not necessarily of any lower quality than cGMP ingredients. Because the responsibility of ensuring the quality of an in-process material lies with the cGMP manufacturer, the quality requirements are also determined and verified by that facility.

21 CFR §211.110 states that:¹⁵

“In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.”

The EudraLex has similar language, although it refers to starting materials instead of in-process materials (a “starting material” is any substance used in the production of a medicinal product, but excluding packaging materials, according to the EudraLex Glossary).¹⁶ In Volume 4, section 5.28, of the EudraLex, the process of establishing quality requirements with a supplier is specifically outlined:¹⁷

“The quality requirements established by the manufacturer (cGMP Manufacturer) for the starting materials should be discussed and agreed with the suppliers.”

Usually the relationships between in-process material manufacturers and cGMP customers are fairly transparent which, when the products being sold to the pharmaceutical customers are manufactured in a way that keeps the intended use in mind, helps cut down on potential contamination risks. Practices such as dedicating equipment, performing stability tests and creating detailed specifications support low batch to batch variability and help ensure the safety of products being sold to the medicinal industries. Ultimately, the starting material, or in-process material, manufacturer and cGMP customer need to work together to find a balance between quality and efficiency.

The EudraLex states, with regards to the testing of starting materials, in Volume 4, Section 1.4:¹⁸

“A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that:

(v) Arrangements are made for the manufacture, supply and use of the correct starting and packaging materials, the selection and monitoring of suppliers and for verifying that each delivery is from the approved supply chain;

(vii) Processes are in place to assure the management of outsourced activities.”

The EudraLex goes on to say, in section 7.4:¹⁹

“The Contract Giver (cGMP manufacturer) is ultimately responsible to ensure processes are in place to assure the control of outsourced activities.”

Conclusion

How an adsorbent is used in a cGMP facility drastically affects the quality requirements for that material. For adsorbent applications in production, other than ingredient applications, the USP-NF and Ph.Eur. monographs do not apply and the manufacturing facilities for those adsorbents are not regulated by the FDA or EMA. The quality requirements for adsorbents used in applications such as chromatography, batch extractions and water removal are ultimately determined by the cGMP manufacturers. Cooperation between a cGMP manufacturer and a supplier usually leads to a quality/efficiency based approach used by pharmaceutical companies to meet the needs of their customers, the general public.

References

1. The Concept of Pharmaceutical Quality. 6, s.l. : American Pharmaceutical Review, 2004, Vol. 7, pp. 10-15.
2. U.S. Pharmacopeia 41 National Formulary 36. s.l. : The United States Pharmacopeial Convention, 2018. p. xi. Vol. 1.
3. 21 CFR §210.1 . [Online] December 20, 2018. [Cited: January 09, 2019.] https://www.ecfr.gov/cgi-bin/text-idx?SID=bb2186b14c174f8846258d4c73c55b01&mc=true&node=se21.4.210_11&rgn=div8.
4. Quality in the pharmaceutical industry – A literature review. Haleem, Reham M., et al. 5, s.l. : Saudi Pharmaceutical Journal, 2015, Vol. 23, pp. 463-469.
5. 21 U.S. Code § 331. [Online] December 13, 2016. [Cited: January 09, 2019.] https://www.law.cornell.edu/uscode/text/21/331.
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8. History. International Council for Harmonization. [Online] [Cited: January 09, 2019.] https://www.ich.org/about/history.html.
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10. New Drug Application (NDA). U.S. Food & Drug Administration. [Online] March 29, 2016. [Cited: April 23, 2019.] https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/newdrugapplicationnda/default.htm.
11. 21 CFR §210.3. [Online] December 20, 2018. [Cited: January 10, 2019.] https://www.ecfr.gov/cgi-bin/text-idx?SID=bb2186b14c174f8846258d4c73c55b01&mc=true&node=se21.4.210_13&rgn=div8.
12. U.S. Pharmacopeia 41 National Formulary 36. s.l. : The United States Pharmacopeial Convention, 2018, Vol. 3, p. 5559.
13. InspectionGuides. U.S. Food & Drug Administration. [Online] November 25, 2014. [Cited: January 09, 2019.] https://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm170827.htm.
14. A New Definition for API Starting Materials. Giralt, R. 6, s.l. : Pharmaceutical Technology Europe, 2004, Vol. 16.
15. 21 CFR §211.110. [Online] December 20, 2018. [Cited: January 10, 2019.] https://www.ecfr.gov/cgi-bin/text-idx?SID=f90183232a358a38edd4d8bcf90f8b72&mc=true&node=se21.4.211_1110&rgn=div8.
16. EudraLex. European Comission. [Online] January 2015. [Cited: January 09, 2019.] https://ec.europa.eu/health/documents/eudralex_en.
17. EudraLex Volume 4 Chapter 5. [Online] August 13, 2014. [Cited: January 10, 2019.] https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/chapter_5.pdf.
18. EduraLex Volume 4 Chapter 1. [Online] June 1, 2012. [Cited: January 10, 2019.] https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/vol4-chap1_2013-01_en.pdf.
19. EudraLex Volume 4 Chapter 7. [Online] June 28, 2012. [Cited: January 10, 2019.] https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/vol4-chap7_2012-06_en.pdf.

Author biographies

David O. Rosenberg is currently a Business Segment Manager at Porocel Industries LLC. Previously, he was a Validation Consultant for Johnson and Johnson and a Validation Supervisor at GlaxoSmithKline. He earned a BS in Biochemistry and his Masters in Organic Chemistry from the University of Southern California.

J. Adrian Hawkins is currently Porocel Industries’ Technical Operations Manager. Previously, he was Technical and Business Director of ITW-Kester and Director of Commercial Development and Technology for Eastman Chemical Company. Dr. Hawkins has published more than a dozen scientific papers and reviews and has been issued more than two dozen US and international patents. He earned a BS in Chemistry and his Ph.D. in Physical Organic Chemistry from the University of Arkansas.