GMP Fentanyl and Fentanyl Analogs

Introduction

Fentanyl and its analogs have seen an increase in demand and global requirements in recent years. These µ-opioid receptor agonists are classified as schedule II drugs by the US DEA due to their potential for abuse. Due to this classification, a DEA registered manufacturer is required. Cedarburg Hauser Pharmaceuticals (CHP) is registered with the DEA to manufacture controlled substances, and has experience manufacturing GMP fentanyl and its analogs. Continue reading for more information on these compounds, and request a free project evaluation if you have a need for GMP fentanyl and one of its analogs.

Fentanyl

Fentanyl (Figure 1) is a synthetic pharmaceutical first synthesized in 1962, and currently marketed for use in surgical anesthesia and pain management, where it acts as a µ-opioid receptor agonist. Fentanyl continues to be of clinical interest today. A number of companies are investigating alternative delivery methods, and there are a handful of fentanyl products at various stages of clinical development. Most of these products are aimed at delivery through the mucous membrane of the mouth. A separate, unique delivery system involves the covalent attachment of opioid agonists such as fentanyl to water-soluble oligomers. This offers a number of advantages over traditional drug delivery methods including improved pharmacokinetics, decreased toxicity, and controlled drug release. CHP has experience conjugating controlled substances to polymers, as described in this case study.

According to data published by the International Narcotics Control Board (INCB), the 2012 estimated global requirement for fentanyl is approximately 4.49 metric tons, representing an increase of around 20% since 2008. Over 50% of this total is scheduled for production in the United States (1.42 metric tons) and Belgium (1.00 metric tons).¹ Qualified manufacturers are needed to meet the growing demand. CHP is an experienced manufacturer of fentanyl and has filed a drug master file (DMF) for both fentanyl and fentanyl citrate with the FDA.

Fentanyl is currently classified as a schedule II compound under the US Controlled Substance Act. As a controlled substance, manufacturers of GMP fentanyl need to be registered with the DEA, and obtain a quota for the approved manufacturing of the drug substance. CHP has an excellent DEA inspection history, and has established processes and systems for the compliant handling, storage and manufacturing of fentanyl.

Fentanyl Analogs

Since the discovery of fentanyl, researchers have developed a series of other 4-anilinopiperidines which are structural analogs to fentanyl, and also act as µ-opioid receptor agonists. Of these analogs, alfentanil, sufentanil and remifentanil have found clinical use in humans. The other, carfentanil, is used in veterinary settings. These analogs each retain the N-ethyl spacing group, which has proven to be important for high affinity to the µ-opioid receptor. The N-phenylpropanamide group is also retained in each analog, which is thought to play a role in interactions with the TM-VI recognition sequence.²

Alfentanil

Like fentanyl, alfentanil is typically used for anesthesia. In alfentanil, the N-phenylethyl group of fentanyl is replaced with a modified tetrazole group, and an ether group is substituted on the piperidine ring (Figure 2). These modifications result in a fast-acting µ-opioid receptor agonist with onset nearly four times faster than fentanyl, but with a reduced potency. Approximately 39.7 kilograms are estimated as a global requirement for 2012.¹ However, API manufacturing shortfalls have resulted in drug shortage. Additional manufacturing will be required to meet the shortfall. Like fentanyl, alfentanil is classified as a schedule II compound by the DEA, so a DEA registered company will need to manufacture the compound. A national manufacturing quota of 15 kg was set by the DEA for 2012.

Remifentanil

Remifentanil is another in a series of fentanyl analogs. It is primarily used in anesthesia and pain relief, but has also been used as a sedative. Remifentanil is one of the more unique fentanyl analogs (Figure 3), with an ester group in place of the N-phenethyl. The result is a sterically smaller compound with similar pharmacological properties. It is the shortest acting opioid currently on the market. The INCB estimates the global requirements of this schedule II compound to be approximately 143 kilograms for 2012, with the United States manufacturing just 3.5 kg of material. 85% of current material requirements are being met at manufacturing facilities in Belgium, the United Kingdom and China.¹

Sufentanil

Sufentanil is an analog that is 5-10 times more potent than fentanyl. The benzene ring of the N-phenethyl group of fentanyl is replaced with a thiophene in sufentanil (Figure 4). Sufentanil is currently marked for surgical and pain management applications. Additional clinical trials are underway to further investigate sufentanil’s use in pain management applications. In one particularly interesting Phase II trial, AcelRX Pharmaceuticals combines sufentanil with triazolm, a benzodiazepine drug, and is designed to provide non-invasive mild sedation as well as pain relief. Global requirements for sufentanil are currently estimated at approximately 15 kilograms for 2012. 33% of this requirement (5 kg) is required for use in the United States. Despite the large requirement, only 19% of the global stock of the drug is manufactured within the United States.¹ Like the other fentanyl analogs, sufentanil is also a schedule II compound, and requires DEA registered manufacturers such as Cedarburg Hauser to meet the growing demand.

References

1. Narcotic Drugs Estimated World Requirements for 2012 – Statistics for 2010, 2011, http://www.incb.org/incb/en/narcotic-drugs-technical-report_2011.html (last accessed 4/6/2012).
2. Subramanian, G.; Paterlini, M.G.; Portoghese, P.S.; Ferguson, D.M. J. Med. Chem. 2000, 43, 381-391. (Access Here)