At INTERPHEX 2016, Wellspring Pharma Services, a provider of formulation, development, and clinical supply to commercial and clinical manufacturing, will be participating in two presentations:

1. “What You Need to Know: CMOs and the Manufacture of Controlled Substances”

• Presented by: David Mayers, President of Wellspring Pharma Services
• April 27 at 10:15 am at the Crystal Palace (CP-2)

2. “The Importance of Effective Tech Transfer and Validation Strategies with CMOs”

• Presented by: Norm Fong, Technical Transfer Manager, Business Development of Wellspring Pharma Services
• April 27 at 10:30 am at booth 1177, Exhibit Hall

Mayers and Fong participated in an exclusive Q&A with Pharmaceutical Processing to delve into the topics of these two presentations further.

Below are the edited responses.

Q: Can you provide a general synopsis of the types of requirements and regulations faced by contract manufacturers when entering the market for controlled drugs?

Mayers: The regulations for a CMO, manufacturers, or importer/exporter are governed by regulatory bodies such as the DEA in the U.S. or the Office of Controlled Substances in Canada. We are required to handle, store, transport, and destroy material in a regulated manner so that we maintain appropriate security, accountability, traceability, and material management to prevent diversion and ensure the protection of the material and the public. The use of the material must be for an approved purpose and the quantities imported are defined.

Q: Considering the entire contract market, what percentage of CMOs in the U.S. today manufacture controlled substances? Has that percentage changed over the last decade, either higher or lower?

Mayers: The overall number has gone down as regulations and costs have escalated—even with increased capacity as a result of mergers and available facilities. In addition, many of the major pharmaceutical companies in the industry have wanted to maintain internal control to ensure security of their supply chain.

Q: Have any CMOs backed away from handling controlled substance manufacturing in recent years? If so, what was the main reason?

Mayers: The increased scrutiny and internal controls that are required (especially with higher risk molecules) have increased the efforts and costs to maintain production facilities capable of producing and storing controlled substances.

Q: Five years ago the world market for controlled drugs was said to be more than $20 billion, with more than 60 percent share in the U.S. How do those statistics compare in 2016?

Mayers: What we are seeing is the market for controlled drugs sitting at around $26 billion as of 2013. With that we can see that this has continued to rise with the increased use of these products as well as the advent of new dosage forms, specifically those that address abuse deterrence. 

Q: Describe the breakout of Schedule I through Schedule V drugs. Are any Schedule I drugs considered appropriate for medical use or does that designation start at Schedule II down?

Mayers: Each schedule groups products based on several factors such as risk, potency, etc. 

Schedule I through IV drugs are defined as follows:

I. Drugs not currently accepted for medical use and with a high potential for abuse. Schedule I drugs are the most dangerous drugs of all the drug schedules with potentially severe psychological or physical dependence.

II. Drugs accepted for medical use with a high potential for abuse, and with use potentially leading to severe psychological or physical dependence. These Schedule II drugs are also considered dangerous.

III. Drugs with a moderate to low potential for physical and psychological dependence. Schedule III drug abuse potential is less than Schedule I and Schedule II drugs but more than Schedule IV.

IV. Drugs with a low potential for abuse and low risk of dependence.

Definitions from: www.dea.gov/druginfo/ds.shtml.

Q: Have any drugs in recent years been shifted between categories (i.e., previously considered prescription medications and now regarded as controlled substances)? If so, what are some examples and what was the prime motivating factor behind the shift?

Mayers: Each country is different and the change is based on abuse, use of the material, etc. 

Q: Where does medical marijuana fit into the controlled substance picture, especially since it is legal in some states but banned by the federal government? 

Mayers: Regulations in Canada are different than in the U.S. In Canada, there is a separate set of regulations. In the U.S., cannabis is a Schedule I drug under the Controlled Substances Act of 1970, but states may choose to decriminalize it. Currently ten states, Guam, and Puerto Rico have legalized medical marijuana.

Q: What monitoring requirements must CMOs follow during the manufacturing and handling of controlled drugs?

Mayers: It depends on the material, but, in general, the movement, surveillance, secure storage (safes), and reconciliation (material balances) are managed in a way to ensure there is no loss or diversion.

Q: What kind of training is required for CMO personnel authorized to handle or participate in the manufacturing process of controlled substances?

Mayers: In most countries, you must be registered with the government and hold credentials so that you are able to appropriately oversee such operations. A background check is often required, and, in some cases (as in Japan), certification by a physician is required. Each employee is trained accordingly to our SOPs to comply with the heightened requirements associated with handling controlled substances.

Q: How are tech transfer changes typically monitored from beginning stages to final implementation? 

Fong: At WellSpring, we assign a project manager starting from the beginning stages who is maintained until completion. There is a kickoff meeting initiated by the project manager and there are numerous activities happening at the same time with some of these activities dependent on each other while others are independent. The meeting includes the resources and activities required as well as due dates and milestones. If there are required changes, the project managers coordinate and document all these activities until implementation, and usually beyond into commercial stages. With this organized process, we ensure all activities are completed accurately and on-time.

Q: What are some of the big mistakes that companies often make during tech transfers, and how can this be avoided? 

Fong: CMOs are very experienced with many different types of products and processes. As a result, CMOs can identify issues early and mitigate risk, in many cases by proactively resolving. If all the necessary information isn’t communicated during the technical transfer, or information is outdated or incomplete, vital information may be omitted. It is essential that the CMO develop a strong working relationship of mutual trust with the drug owner so that the drug owner feels comfortable working alongside the CMO throughout the transfer.

Q: What are some of the key steps involved in an effective tech transfer? 

Fong:

• Identify the raw material and make sure that they are the same type (if possible have the same material from the same source)
• Identify critical process parameters
• Assess the equipment for size, class, and sub-class
• Have approved protocols in place to identify what is to be done and why
• Complete and approve reports to summarize all findings
• Assess analytical methods and transfer or validate as appropriate
• Perform packaging line trials, stability, cleaning validation, health and safety review, and gap analysis

Q: What are some of the guidelines and regulatory bodies that come into play during tech transfers? How do they impact and oversee the overall process?

Fong: Guidelines from the following regulatory bodies help the tech transfer process:

• The U.S. FDA SUPAC (Scale-up and Post-Approval Changes) guidances to assist in selecting and comparing the correct equipment.
• The new process validation (PV) guidelines help with the validation by dividing the PV in three stages and describing what is required at each of the three stages.

Q: How does the tech transfer process compare in different countries? 

Fong: The tech transfer process is not really different from one country to another. CMOs work with all different companies from different countries that market products in countries all around the world. The transfer is the same, but there are some differences in the regulatory requirements. The process may need to be slightly modified for some markets.

Q: What strategic goals must be set across the operation to achieve consistent quality? 

Fong: The quality found in each product is the culmination of proper experience, training, documentation, and execution all defined within our Quality Management System. Quality is established in our mission and flows through our values such that each employee ensures consistent and expected quality and compliance in our processes.

Q: Could you detail a few validation strategies with CMOs?

Fong: The strategies differ depending on the situation. If extensive development was performed to understand the process, identify the critical process parameters and the control strategies, the validation becomes easier. Several successful lots of validation batches are produced to complete the validations. If there are several strengths and they are very similar, then a matrix approach can be used—where only a few validations batches are produced on each strength, or just the higher or lower strengths.

Q: What are some of your favorite INTERPHEX memories?

Fong: The first time I attended INTERPHEX and seeing how large the complex is. I was amazed to see so many companies with all their machines on display.

Click here to learn more about Wellspring Pharma Services! To view the live INTERPHEX show floor plan, click here.

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