Process validation is a critical regulatory requirement in pharmaceutical manufacturing. It ensures that a production process consistently yields products of predetermined quality and safety. The goal is to verify that all stages of drug production—from raw materials to final dosage forms—meet established quality standards.  

For drugs with FDA Orphan Drug Designation (ODD), Breakthrough Therapy Designation (BTD), and EMA PRIority MEdicines designation (PRIME), all clinical, non-clinical, and CMC requirements are still required for regulatory approval, despite being on pathways for an expedited approval process. In the case of urgent or immediate public interest, process validation may be conducted concurrently with manufacturing the commercial small molecule or biologic product to expedite product availability for patients. This process can be initiated during the review period of the biologics license application (BLA) or new drug application (NDA) prior to approval. 

In this blog, we review the stages of process validation, provide essential insights for sponsors considering the concurrent process, and outline some specifics for small molecules and biologics. 

Stages of process validation

Process validation involves three distinct stages as described in the 2011 FDA guidance, “Process Validation: General, Principles and Practices.”ⁱ These include:  

• Stage 1: Process design – the commercial manufacturing process is defined based on knowledge gained through development and scale-up.  

• Stage 2: Process qualification – the focus shifts to ensuring that the process is robust and capable of consistently producing products that meet predetermined quality standards. This stage is commonly referred to as the PPQ (process performance qualification).   

• Stage 3: Continued process verification – involves monitoring and verifying the process during routine production. 

Key considerations for concurrent process validation

In cases where expediting the drug approval process is in the public’s best interest, the PPQ may be performed concurrently with commercial manufacturing.ⁱⁱ When appropriately applied, concurrent validation provides a powerful tool to address impractical limitations of bringing new drugs and biologics to market. 

Sponsors considering a concurrent validation approach must have alignment internally across the Manufacturing, Pharmaceutical Development, Technical Operations, and Quality Assurance teams, along with external alignment with governing regulatory bodies. In fact, regulatory authorities typically expect agreement on concurrent validation prior to BLA submission; otherwise, there could be review and approval delays. 

The rationale and approach for concurrent validation must be documented in an approved Master Validation Plan (MVP), which should outline the requirements for navigating each step of the validation cycle. It should also include a well-defined risk assessment of the following parameters:  

• The manufacturing history of the process from inception through the pivotal clinical trial supply. 

• The quality of data from Stage I validation activities.  

• Prior PPQ knowledge and experience with similar products. 

It is important to note that if the manufacturing process is being transferred to a new contract development and manufacturing organization (CDMO), the risk assessment might not support a concurrent approach. If, on the other hand, the process is being performed at the facility where it was developed as part of a platform manufacturing process, the risk assessment is likely to be supportive of a concurrent approach. 

Like prospective validation, concurrent process validation requires all equipment and utility qualifications to be complete prior to the execution of the PPQ, including all cleaning, analytical, and computer system validations. Furthermore, completion of Stage 1 activities should have provided a thorough understanding of the critical process parameters and potential critical quality attributes.  

Concurrent validation for small molecules

Establishing the requirements  

Process validation requirements for small molecule drug development are contained within the FDA’s Compliance Policy Guide (CPG) Sec. 490.100 titled, “Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval.” ⁱⁱⁱ  

Under the 505(b)(1), 505(b)(2), or 505(j) pathways for small molecule approval, an initial conformance batch (known as the PPQ batch) is not required to be manufactured prior to approval, per the CPG. The PPQ conformance batches are manufactured prior to commercial distribution and align with Stage 2 process validation requirements. Unlike a BLA submission, the NDA process allows conformance batches to be produced post-approval to account for any changes to the process made during NDA review. In these cases, conformance batches post-approval must be manufactured prior to commercial distribution of the approved product.  

Reviews and inspections of concurrent PPQ 

Although process validation protocols and results are not reviewed as part of an NDA, they are evaluated during the pre-approval inspection (PAI), if conducted. If conformance batches are deferred to post-approval, the FDA will require a post-approval inspection within the first year of commercial distribution. If deficiencies are found, additional work and information will be required to ensure commercial distribution or continued distribution of the product.  

During the PAI, the FDA will evaluate the sponsor’s justification for concurrent release, the protocol/plan and available data, and the sponsor’s plan for monitoring distributed batches, including provisions for rapid response to failures. Based upon these criteria, the FDA will determine if concurrent validation is appropriate for the product. If inspected during a post-approval inspection, the protocol and available data will be reviewed for adequacy, as will the quality systems in place to evaluate the generated data.  

Key advantages of concurrent PPQ for small molecules 

Concurrent validation offers key advantages for small molecules and is essential for products with short shelf lives, such as radiopharmaceuticals, which need immediate distribution and use. Additionally, drugs with ODD, BTD, and PRIME designation require rapid distribution to meet urgent patient needs and could rely on the concurrent validation approach to ensure timely availability to patients. Financially, however, the conformance batches may prove burdensome for sponsors, particularly in orphan drug products where the costs may outweigh the projected return.  

Concurrent validation for biologics submitted as a BLA or MAA

A biologic drug product under the FDA’s 351(a) approval pathway must undergo Stage 2 of process validation (PPQ) prior to commercialization. While prospective validation is the norm and involves submitting the PPQ data as part of the BLA or marketing authorization application (MAA), concurrent validation could be appropriate in specific cases and occurs after submission, but before market authorization.  

Establishing the requirements  

Many PPQ requirements for biologics are like those for small molecules. However, the following considerations impact the requirements: 

• The complexity of most biological products means that it is typical for multiple batches to be manufactured at relatively small batch sizes during development, especially for ODD or PRIME designated products.  

• Higher variability of critical quality attributes (CQAs) for biologics requires robust characterization of critical process parameters, again translating to higher numbers of development batches than for small molecules.  

• Comparability needs are frequent due to higher likelihood of scale, equipment, and manufacturing facility changes. Regulatory guidances have been published to address these needs, e.g. “ICH Q5E – Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process” ^iv and “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products.” ^v   

Therefore, development data available at BLA/MAA submission is likely to fully support Stage 1 PPQ and enable concurrent Stage 2 as appropriate and agreed with the regulatory agency. 

Reviews and inspections of concurrent PPQ 

Protocols for concurrent validation of a biologic must be submitted with the BLA, as is the proposed manufacturing schedule. Note that pre-approval inspections for biologics are referred to as pre-licensing inspections (PLI). Other inspectional requirements mimic those for small molecules.  

Key advantages of concurrent PPQ for biologics 

In addition to the advantages outlined for small molecules, concurrent validation is imperative for biologics intended for treatment of orphan and ultra-rare conditions such as monogenic disorders, given their typically small patient populations.  

Early planning and proactive feedback

Meeting with regulatory agencies in advance of submitting a marketing application is strongly recommended to obtain their feedback and agreement on the approach and timing of the proposed concurrent validation exercise. Further, sponsors should provide regulators with a well-crafted validation plan that outlines proposed timing and a clear risk assessment to ensure a successful concurrent PPQ approach. 

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Premier Consulting’s CMC experts bring decades of experience in supporting sponsors with their process validation planning. For support with developing your plan, contact us.  

 

Authors:

Olu Aloba, Ph.D., VP, CMC Services

Ryan Key, Senior Director, Regulatory Affairs, CMC  

 

References:

i https://www.fda.gov/files/drugs/published/Process-Validation–General-Principles-and-Practices.pdf 

ii EMA–FDA joint Q&As on Quality and GMP aspects of PRIME/Breakthrough therapy applications, 4 December 2023, EMA/CHMP/531552/2-23 

iii https://www.fda.gov/media/71756/download 

iv https://www.fda.gov/media/71489/download 

v https://www.fda.gov/media/170198/download