Easing Process Validation Rules for Small-Volume Manufacturers


Last month the FDA announced the creation of a task force to investigate rising drug shortages and identify actions to prevent and address them. While not at the levels experienced in 2012, recently, drug shortages for specific medications, such as the EpiPen, Lidocaine and drugs for the treatment of migraines and Parkinson’s Disease, have caused numerous difficulties for clinicians, healthcare facilities, and most importantly, patients.

The Food and Drug Administration defines a drug shortage  as a “period of time when the demand or projected demand for a medically necessary drug in the U.S. exceeds its supply.”

Drug shortages are caused by many factors, including difficulties in procuring raw materials, regulatory issues and manufacturing problems, which force a freeze in production in order to address the problem. One recent example is Hurricane Maria in Puerto Rico, which caused severe damage to production facilities there.  And, when drugs are in short supply and produced by a biotech firm with few competitors, demand quickly outpaces supply.

In addition to the obvious problems when patients are denied critical, often life-saving drugs, drug shortages also cause price increases.  According to the Annals of Internal Medicine, in the 11 months after the shortage of drugs for the treatment of migraines and Parkinson’s Disease, prices increased by up to 20% compared with 9% in the absence of a shortage.

Removing the One-Size Fits All Approach to Regulation

The FDA is walking a fine line, working to balance the need for strict regulatory control to make sure drug products are produced for maximum efficacy and safety, while enabling products to be approved and delivered in a timely manner to meet patient needs.

Yet, the FDA needs to consider the size of the drug product and the firm who manufactures it when setting regulatory requirements for process validation, equipment used and other guidelines. What might be easy for a large pharma firms to undertake in order to pass FDA muster, may require exorbitant amounts of money, resources and effort for smaller ones.

Below are three key factors that make FDA approval often challenging for Contract Development and Manufacturing Organizations (CDMOs) producing small-volume batches:

Pricing. Especially in the case of drug products that treat a relatively small segment of the population, small batches of active ingredients or finished drug products –– are all that is needed to meet specialized patient demand. Surprisingly, while cancer has been seen as a major health threat affecting large amounts of the population, in actuality the cancer population is quite small in comparison to other diseases.  Oncology drugs often are not cost effective for smaller manufacturers to produce given the regulations required to meet FDA approval.

In this case, since profitability is not possible with limited batch drug products, it boils down to becoming an ethical decision, where CDMOs see it as a moral obligation to produce drugs that will save lives – albeit within a small population

Validation.  For manufacturers producing small volumes, they only get paid for what they deliver, and that amount is typically very small – usually one-to-two kilograms to satisfy production needs. Yet, FDA regulations require several batches  to demonstrate adequate batch data to show your process is under control.  Smaller CDMOS must absorb the cost of three batches when only one batch is required to satisfy demand.  Likewise, when a CDMO is submitting a Drug Master File (DMF), a minimum of three batches is needed to prove stability.

Raw Materials. Small volumes of drug products are derived from raw materials, often natural substances, in which impurities can fluctuate according to where they are harvested, weather and temperature changes and other uncontrollable factors.  While these challenges affect manufacturers of all sizes, large pharma firms have more supplier options and carry more weight with them to offset any issues that impact the purity of raw materials.

The FDA is working to fast-track certain drugs in short supply, adding resources and other measures, but progress has been slow. Trade groups have formed to pool resources and put pressure on the FDA and work collaboratively to solve the drug shortage dilemma and make regulations more realistic and productive.

For example, we at PCI Synthesis are part of the Bulk Pharmaceutical Task Force (BPTF), an industry trade organization representing manufacturers of active pharmaceutical ingredients (APIs), intermediates and excipients. It was created as an affiliate organization of the Society of Chemical Manufacturers & Affiliates (SOCMA) to address regulatory and plant operations issues related to current Good Manufacturing Practices (cGMP) compliance.

As a result of our efforts, just recently the FDA published draft guidance on how to make post-approval changes to information on drug substances. In the past, this  guidance for post-approval changes to drug products, was scarce, yet the industry clamored for clearer information, and this new guidance provides the specifics on what is required.

Most drug substance and drug product manufacturers both large and small understand the gravity of making materials to be consumed by humans, so they’re not opposed to following the rules. Yet, by working in close partnership with the FDA and others in the industry, steps can be taken to level the playing field and make it easier for manufacturers of all sizes to fulfill patient demand and remove shortages of life-saving drugs, safely and effectively.

We’d love to hear your thoughts on the subject.  You can reach us at (978) 462-5555.