In our earlier blog on US Food and Drug Administration’s (FDA) current thinking on post-approval changes, we discussed, what application types do the FDA’s industry guidance on post-approval changes to drug substances applies to and what types of changes does it emphasize. As there are multiple changes discussed in the guidance, decoding each type of change, studying the possible effects and keeping the agency informed about them is crucial to maintain continued marketability of the drug product. Elaborating on the changes, the guidance further explains what exactly each type of change entails. To give you a detailed account of each change, here we discuss them in detail as opined by the FDA.

1. Facility Changes, Scale Changes and Equipment Changes

Even a single specification of change has the ability to alter the end result of the entire drug formulation. The changes in either facility, scale or equipment, should be reported or informed to the health authority. It should be noted that while making these changes, adjustments done to process parameters should only be limited to those needed to accommodate new equipment. A detailed account of facility, scale and equipment changes are as follows:

1. Facility Changes:

Facility changes are the changes in location of site of manufacture of intermediates and unfinished and final drug substances for both the company owned and the contract manufacturing facilities. The applicant or DMF holder is responsible for ensuring that any new facility is aligned with current good manufacturing practice (cGMP) regulations. Typical facility changes that must be reported are, but not limited to:

• Addition of a new contract manufacturing facility for an intermediate by the drug substance manufacturer or an existing contract manufacturer
• Addition or relocation of an in-house intermediate manufacturing facility to a different campus
• Transfer of new contract manufacturing facility for an intermediate by the drug substance manufacturer or an existing contract manufacturer
• The addition or relocation of an in-house intermediate manufacturing facility to a different campus
• Transfer of an additional manufacturing step to a facility already being used got the other manufacturing steps
• Change of facility for the final purification or final manipulation of the drug substance
• Addition of an alternative manufacturing facility for the drug substance

2. Scale Changes:

Scale changes are the changes pertaining to the batch size outside the validated scale for intermediates, and the finished/unfinished drug substance. The section is relevant to changes of scale that use equipment of the following characteristics.

• Same equipment as listed in the current master batch record (MBR)
• Equipment that differs only in capacity from the equipment listed in current MBR
• Equipment of same construction material, design and operating principle as equipment listed in the current MBR

3. Equipment Changes:

It is related to changes in equipment that is of a different construction material, design or operating principle than the equipment listed in current MBR. Changes in equipment at an existing manufacturing facility must be reported. In case the organization has a contract manufacturer, a quality agreement must be made between the parties to ensure that changes in equipment made at the contract manufacturer are reported to the master file holder. A change to new equipment with different construction material, design or operating principle has greatest potential to adversely affect the physical properties of the drug substance if this changed equipment is used during or after the final step or after subsequent processing procedures such as,

• Isolating the drug substance
• Drying the drug substance
• Reducing the particle size of the drug substance

2. Specification Changes

This section entails information about specification changes to raw materials such as reagents and solvents, intermediates, drug substances including unfinished drug substances and changes to controls for critical steps (e.g. tests for control of reaction events).  

1. Specification changes to raw materials and intermediates: Generally, specification changes can be categorized into:

• Changes made to comply with compendial changes, including the following:
  • USP Monograph or other compendial monographs31 for a raw material availability
  • USP Monograph or other compendial monographs for a raw material status update
• Changes that provide greater assurance of quality:
  • Tightening acceptance criteria
  • Adding a new impurity control
  • Revising an existing analytical procedure with an improved procedure
  • Revising specifications associated exclusively with improved analytical procedures
• Other specification changes:
  • Relaxing acceptance criteria
  • Deleting a test
  • Replacing an existing analytical procedure with a new procedure
  • Revising specifications associated with changes in supplier/grade of reagents or solvents, including the use of recycled solvents

2. Specification changes to drug substances:

These changes to drug substance or unfinished drug substance include additions, deletions, or changes to analytical procedures. The exact nature of specification changes are as follows.

• When USP monograph becomes available or is updated, the drug substance’s specifications should be updated with the compendial standards as appropriate
• Appropriate justification must be provided whenever an existing test is deleted, or routine test is changed to a skip test

3. Manufacturing Process Changes

Changes to the manufacturing process at/after final solution step are considered to have high potential to adversely affect the impurity profile and physical properties of the drug substance. This section includes a range of such process-related changes.

1. Changes that do not involve the route of synthesis:

• Changes in unit operations such as addition, deletion, change in the order, or repetition of an existing unit operation on a routine basis
• Addition or deletion of raw materials like reagents and solvents or ancillary materials like resins, processing aids etc.
• Changes in solvent composition (other than for an analytical procedure covered in specification changes)
• Changes to process parameters such as temperature, pH, reagent stoichiometry, time etc. that are not related to scale or equipment changes

2. Changes in the route of synthesis in one or more steps:

In general, these changes are considered to have a moderate to high potential to adversely affect the impurity profile of the drug substance. The manufacturing process should be validated using the new route of synthesis. Impurity carryover studies and spike/purge studies should be conducted as appropriate. Control of mutagenic impurities in or expected to be in the final drug substance should be evaluated according to ICH M7 (section 4.1)

4. Starting Material Changes

Changes in the vendor of the starting material may have a potential to adversely affect a drug substance’s impurity profile depending on the starting material and its proximity to the drug substance. Changes to the route of synthesis or manufacturing process of the starting material that result in changes to the starting material specification could have a higher level of risk. Good manufacturing practice as described in ICH Q7 apply to the changes in Active Pharmaceutical Ingredients.

5. Contained Closure System Changes

The instructions on what are considered as contained closure system changes and how to deal with them are provided in the industry guidance released by the FDA. Organizations making post-approvals changes are instructed to follow the provided link.

6. Multiple Changes

Multiple changes are those changes that involve a combination of changes dealt so far. For example: a change to a new source of drug material, which brings in a change in facility, and any number of changes in manufacturing process potentially including a different route of synthesis can be referred to as a multiple change.

With extensive information on the glossary, identification of the post-approval changes to drug substances, and how to report them, the guidance may seem complex to decode. Hence, the needed action for organizations is to consult a Regulatory Affairs expert to thoroughly discern the criteria for post-approval changes and to proceed cautiously towards compliance. Be informed. Be compliant.