Solutions to Common Reg CMC Issues

Regulatory CMC Issues Faced During Pharmaceutical Development

Companies face various questions and issues during the pharmaceutical development which have Regulatory CMC component to them. Below are list of a very common issues that most companies face during the development of their new drugs. Only a high level overview is presented here and is meant to present general recommendations. Every case is different so please contact Rafe Pharma for an in-depth scientific discussion.


Designation of the Regulatory Starting Material

How to assign the Regulatory Starting Material (RSM) and which compound to assign as the RSM is one of the key decision that are made during drug development. The key issue to note is that the GMP starts from RSM so all the synthesis steps and testing should be done under GMP after the RSM. From FDA and other health authorities’ perspective, they want companies to go back as much as possible in the synthesis route as possible and assign a RSM as early in the synthesis route as possible. The reason for this thinking is that since there will be more steps done under GMP, more control and knowledge will be gained about the synthetic route and its ability to form and purge impurities during synthesis.  They key issue for agencies is of course the quality of the drug substance and the impurities profile therefore the earlier you start your synthesis and testing under GMP, the more knowledge you will gain about your process and the impurity profile.

One other major reason behind agencies’ request to assign a compound in early steps of the DS synthesis is that the supplier and the route of synthesis before the RSM can be changed without notification to agencies before and after the NDA approval.  This becomes a major risk factor for the agencies since they worry that a change in the route of synthesis before the RSM could generate unknown and unqualified impurities that end up in the DS hence a quality issue for the product.

Starting GMP early in the route of synthesis implicate higher cost and some contract manufacturers are not willing to start GMP early since due to their facility, QC system or procurement issues. As sponsor, you may end up in situations where you cannot find any supplier who can provide the GMP quality starting material that you need. In this case, you should get involved and help your supplier to get the system and procedures in place to start the GMP from the starting material or pay the higher cost of goods to a manufacturer who can supply what you need.

There are a lot of analytical work also involved in the GMP so a balance should be found to alleviate agencies concern and at the same time avoid having a very cumbersome DS synthesis.

Rafe Pharma can help you to evaluate your situation and provide advice on how to assign your RSM.


Potential Genotoxic Impurities (PGI)

During the synthesis of almost all the small molecules, there is a risk of using a potential genotoxic compound (or starting material) or forming potential genotoxic impurity (PGI) during synthesis. Almost all the companies with small molecule compounds in their development pipeline have to deal with the PGI issue.

PGI is less of an issue for drugs for life threatening diseases or for diseases where patient are not expected to live more than 5 years. For these drugs and patient population, Health Authorities’ bar of expectations is lowered pertaining to permitted amount of the PGI in the drug. The reason is that the risk for developing cancer by consuming genotox impurities is calculated assuming a life time (chronic) consumption of the drug. Since the patients with life threatening diseases are not expected to live more than 5 years, the risk of developing cancer is decreased significantly. Also some of these patient might have already have cancer so the PGI cannot cause a new cancer.

ICH M7 guideline talks about how to manage the PGIs. Table 1 has the classification of the PGIs and the proposed action plan.

Table 1: Impurities Classification with Respect to Mutagenic and Carcinogenic

Class Definition Proposed action for control
1 Known mutagenic carcinogens Control at or below compound- specific acceptable limit
2 Known mutagens with   Control Control at or below acceptable unknown carcinogenic potential limits (appropriate TTC)
3 Alerting structure, unrelated to the   Control Control at or below acceptable unknown carcinogenic potential limits (appropriate TTC) or conduct bacterial mutagenicity assay;If non-mutagenic = Class 5

If mutagenic = Class 2

4 Alerting  structure,  same  alert  in  drug Treat as non-mutagenic impurity substance or  compounds  related  to  the drug substance       (e.g., process ntermediates)  which  have  been  tested and are non-mutagenic
5 No structural alerts, or alerting structure Treat as non-mutagenic impurity


As seen above, the most complicated group is Class 3 where the company has to find out if the impurity is PGI or not. The first thing to do in order to evaluate the mutagenicity of a impurity is to run it through computer systems like DEREK and TOPKAT. Theses system are used to analyze the potential mutagenicity of a structure or group on the impurity (i.e., alerting structure).

If you have a DEREK or TOPKAT positive impurity, the next thing to do is to see if the process can eliminate (purge) it. To do this, you should find out where in the process it is formed, how it is formed, where it is purged and how much of it is purged (e.g., find out how much of the impurity is purged during crystallization).  You should go a so-called spiking/purging study, to evaluate all your PGIs and the process’ capability to form and purge them.

If the computer system detects an alerting structure, it does not mean that the compound is AMES positive.  If the process is not able to purge the impurity, you can do a AMES test to confirm its mutagenicity. If the impurity is AMES negative (which happened often with DEREK positive compounds), then it can be treated as a regular process impurity.

There is a lot of strategy involved in dealing with PGIs. You need a good process chemist, a good analytical person (to develop the methods needed to detect the PGIs) and a good Reg CMC person to deal with this issues for your IND/CTA and the NDA.

Rafe Pharma can help you to evaluate your situation and provide advice on how to deal with your PGIs.


CMC Change During Clinical Study (IND or CTA)

A change to the process to almost always happens during the clinical development. Usually a non-optimized drug substance process or simple drug product formulation is used to initiate the Phase ½ clinical studies since companies do not want to invest much resources on the manufacturing aspect of a drug until the drugs shows some efficacy in clinical studies. After a drug’s preliminary efficacy is established, then the focus shifts towards how to make the drug cheaper and better hence, the introduction of a process change during the clinical studies.

The main focus of agencies during clinical studies is safety (not efficacy). They want to protect the patients who participate in the clinical studies and make sure the drug they receive is as safe as possible. The CMC changes made during the clinical development should be evaluated having agencies’ focus on safety in mind. Therefore, a change in the drug substance or drug product process should not yield new impurities or cause the rise in existing impurities’ levels. If a process change has to be done and it has negative implications on the impurity profile, then thorough qualification studies have to be done in order to support the change and the new (worsened) impurity profile. Changes that have no impact on the impurity profile or a positive impact are of course much easier to justify and support and get agency buy-in.

The main obvious issues with any formulation change is of course its impact on pharmacokinetics (PK). If the safety profile of a drug is established based on a established PK profile, then a change in the PK profile due to new formulation might implicate new side effects or lack of efficacy. A change from capsules (used in early Phase 1/2 clinical studies) to tablets (usually used in Phase 2B and Phase 3) are very common and there are established way to do this.

The key issue to note during the pharmaceutical development is to have as much as possible finalized before the initiation of the pivotal (Phase 3) clinical study. I.e., you should have almost “locked-in” your drug substance and drug product processes and have a “ready to commercialize” formulation before initiating your pivotal (Phase 3) study. You do not want to introduce major changes during your pivotal clinical study since it might invalidate your clinical (efficacy) outcome.

Rafe Pharma can help you to evaluate your situation and provide advice on how to introduce and evaluate your CMC changes.