Regulatory Expectations on Lifecyle Approach to Process Validation

Rose Xu - Senior Pharmaceutical Quality Assessor, OPMA/OPQ/CDER/FDA

Introduction

Process validation is required, in both general and specific terms, by the cGMP regulations in parts 210 and 211, and is a legally enforceable requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)). The basic principle of quality assurance is that a drug should be produced such that it is fit for its intended use. However, during an inspection, citations related to process validation remain amongst the most frequent ones issued by the Food and Drug Administration (FDA). Some examples of inspection citations include inadequate equipment or facility qualifications, inadequate in-process controls and sampling during the process performance qualifications, and inappropriate procedures for managing and implementing manufacturing changes after approval. 

FDA’s current thinking on process validation is available in the 2011 guidance1 for industry: Process Validation: General Principles and Practices. This article provides the author’s perspective on the implementation of guidance principles based on experiences with application review and facility assessment, with specific focus on drug product manufacturing processes for small molecule chemical entities.

Activities Involved in The Process Validation

Process validation involves a series of activities taking place over the lifecycle of the product and process. It starts from the process design stage and extends through commercial production. Successful validation establishes scientific evidence that a process is capable of consistently delivering quality product and contributes significantly to assuring drug quality.

As stated in FDA’s process validation guidance,¹ there are three stages for process validation as discussed here:

Stage 1 – Process Design

Process Design is to build and capture process knowledge and understand variations in raw materials, environment, equipment and also to identify sources of variability in unit operation. Based on the knowledge captured and gained during the development, a control strategy is established to detect and measure the variations.

Product development activities provide key inputs to the process design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway and control strategy. For example, if the active pharmaceutical ingredient (API) or other component in the drug product is very sensitive to light, heat, or prone to oxidation, proper environment controls may be necessary to prevent the potential drug product degradation throughout the manufacturing of the product. If the API is moisture sensitive, a dry blending process may be chosen instead of a wet granulation process for a tablet product. Similarly, for a heat sensitive API, an aseptic process may be chosen instead of terminal sterilization for a sterile drug product. For sterile product, choosing the manufacturing area with correct environment classification is also necessary at this stage. Depending on the unit operation and the potential contamination risk, unit operations may need to be carried out in areas with different environment classifications. If there are multiple products manufactured in the same area, the manufacturer must also evaluate the impact of the manufacturing area size and layout to the drug product to make sure that no potential cross-contamination would occur (see more discussion in PV Stage 2).

At this stage, development activities are usually conducted at a small-scale size, therefore, understanding the sources of variabilities are critical before moving to the next scale-up stage. Quality by Design (QbD) provides a systematic approach that can be used in this design stage to understand the design space of the manufacturing process. Applicants may use Design of Experiments (DOE) studies (based on the risk analysis) as an approach to QbD during the development to gain process knowledge and understand relationships (including multivariate interactions between the variable inputs and the resulting outputs). DOE can help minimize the total number of experiments conducted while maximizing knowledge gained.

After understanding the sources of variation and impact on the manufacturing process and product quality, a strategy to detect and control the variations aligned with the risk it presents to the process and product are expected to be established per 21CFR211.110(a). 21CFR211.110(a) states that “control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product”.

Quality should be built-in through the manufacturing process and controls. The drug product quality cannot be tested into products. A manufacturer must provide a proper control strategy to ensure a robust manufacturing process and to support end product testing as a tool to verify product quality. 

In general, if the manufacturer does not provide the proper control strategy during the manufacturing process but relies on end-product testing, a citation will most likely be issued by FDA.

The ICH guidances also provide general approaches that can be taken for drug development, i.e. ICH Q8² for drug product development, ICH Q11³ for drug substance development, and ICH Q9⁴ for Quality Risk Management.

Stage 2 – Process Qualification

Process Qualification is conducted to evaluate the process design and to determine if the process is capable of reproducible commercial manufacturing. There are two elements for process qualification as described below.

Design of a Facility and Qualification of Utilities and Equipment.

When designing a facility, in addition to the facility systems such as HVAC, Water Systems, Power Supply, Lighting, considerations should also be given to material and personnel flow, the air flow (with dust control), pressurization between rooms, and also equipment locations. 

Some firms start with manufacturing a few drug products first; however, through the years, additional drug products are added to the same facility. cGMP regulations require that facilities where the drugs are manufactured should be of suitable size and construction (21CFR 211.42) to prevent potential cross-contaminations, especially among cytotoxic products and non-cytotoxic products, and also between beta-lactam drugs and non-penicillin drugs (see FDA guidance on Non-Penicillin and Beta-Lactam Drugs⁵). Recently, there have been several FDA 483 observations regarding ‘building lacking adequate space for the orderly placement of equipment...’ and ‘materials which results in the materials mixed up and possible cross-contamination’. In addition, a consideration of easy cleaning should also be given to the wall materials used in critical manufacturing areas, especially those with a high level of sterility assurance requirement.

Per 21CFR 211.63, 21CFR 211.65 and 21CFR211.68, equipment shall be properly designed and calibrated to ensure the equipment is suitable for their intended use and can be reproducibly operated under the proposed manufacturing condition. Equipment qualification involves three stages - Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).

• Installation Qualification (IQ) is to verify the equipment/utility systems are built as designed.
• Operational Qualification (OQ) is to ensure the equipment can operate across the anticipated operating range over proposed production duration.
• Performance Qualification (PQ) verifies that equipment, as connected together can perform effectively and reproducibly based on the intended process and controls.

IQ/OQ should be conducted during Stage 2a. For equipment that is used to manufacture many products with different operational parameters, it is important to consider the use requirements, and incorporate risk management to prioritize certain activities that are conducted during OQ to fulfill the performance requirements for different products. It is often observed on facility inspections and reviewing records requested under Section 704(a)(4) that the equipment was qualified for only a limited operational range (where the current product is operated at), but not extended to the ranges that the machine is capable of operating. When there are new products that are operated at different process ranges, a new OQ (amendment to the current OQ) was found not to be run on the equipment. For example, when conducting OQ of a filling machine, the filling speed (ranges) and filling volume should be shown capable of being held continually accurate as long as would be necessary during routine production for the type of filling configurations. If there are different filling volumes for the same filling configuration, a bracketing approach on the filling volume (usually the lowest and highest filling volume) can be used based on the risk assessment results.

OQ is not a one-time activity. 21CFR211.58, 211CFR211.67 and 211CFR211.68 state that equipment and utility qualification status should be maintained through routine monitoring, maintenance, and calibration procedures and schedules. In addition, equipment should be properly cleaned to prevent the contamination and/or cross-contamination per 21CFR211.67. The cleaning procedure should be validated before commercial production and revisited at appropriate frequency, as needed.

For a sterile product manufacturing, in addition to demonstrating that the equipment can operate at the proposed operational parameters, it is also important to demonstrate that equipment used in the process will be sanitized and/or sterilized and, therefore, suitable for its intended use. Depending on the type of the equipment, different sterilization methods may be utilized such as Ethylene Oxide (EO), radiation, dry heat, and terminal sterilization. During this stage, the equipment is evaluated to ensure it is appropriately sterilized or sanitized before the comprehensive sterility assurance assessment, which includes the drug product, container and closure, is conducted. For aseptic operations, due to the multiple sources of variability from the environment, product, and operators, and other inherent high operational risks, a media simulation that mimics the proposed manufacturing conditions, including all the relevant human interventions, must be conducted to demonstrate sterility assurance. Refer to FDA guidance⁶ on sterile drug product produced by aseptic processing, on facility design and equipment qualification expectations for aseptic process under the cGMP.

Process Performance Qualification (PPQ)

Before releasing product for commercial distribution, process performance qualification (PPQ) has to be conducted and meet all pre-set specifications including in-process testing and final drug product release testing. It combines the intended facility, utilities, equipment and trained personnel with the commercial manufacturing process to establish that design inputs can be met, and the process design is confirmed and verified. A successful process performance qualification (PPQ) signals an important milestone in the product lifecycle. It verifies that equipment, as connected, and operated together can perform effectively and reproducibly, based on the selected manufacturing process, control strategy and test methods and specifications.

To know whether the drug product can be manufactured under commercial conditions, it is important to conduct PPQ at representative conditions by evaluating the equipment or system functions while under load comparable to that expected during routine production.

Even though it is not typically necessary to explore the entire operating range at commercial scale if assurance can be provided by process design data, the PPQ batches are often conducted at the commercial batch scale under the maximum process holding time and over the duration to be used for the commercial production. 

To provide greater assurance around process performance, a higher level of sampling or additional testing maybe warranted during manufacture of PPQ batches per 21CFR211.100(a). Depending on process risk, the sampling and monitoring period could be adjusted based on production volume, process complexity, level of process understanding, and experience with similar products and processes. In general, the sampling plan should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches. 

It should be noted that during process validation, sampling is often more extensive than is typically done during routine production. For example, during tablet compression or filling of a liquid/semi-solid dosage product, in-process control samples are often expected to be taken out at appropriate intervals considering factors such as quality attributes to be tested and the process dynamics. This allows confidence to be built that product uniformity is being achieved across the unit doses, which may be especially important for a product with a tendency for segregation or phase separation. For compounding or mixing unit operation, in-process control samples are expected to be taken out from different locations of the mixing vessel or compounding vessel in order to demonstrate the mixing uniformity or bulk homogeneity. This is especially important for the low drug load products or multi-phase liquid products where a stratified sampling strategy may be appropriate. For a powder blend, refer to FDA level II, Question and Answers on Current Good Manufacturing Practices - Production and Process Controls-Question 15,⁷ for sampling strategy.

It should also be noted that PPQ is not used to develop process parameters used for the commercial production or the acceptance criteria for in process controls, but to verify the selected operational parameters and acceptance criteria to make sure that the process and the process controls remain suitable to support process reproducibility and product quality.

Stage 3 – Continued Process Verification

Continued Process Verification includes activities to assure that the process remains in a state of control during commercial manufacture continually. When the product is being routinely manufactured, unexpected deviations could occur. Therefore, correcting any unplanned departures from the established process will ensure that processes are still operating within established ranges. 21CFR211.165(d) states that “acceptance criteria for the sampling and testing shall be adequate to assure that batches for drug products meet each appropriate specification and appropriate statistical quality control criteria.” As such, any failure of a batch or a component shall be thoroughly investigated. 21CFR211.192 requires that the investigation be extended to other batches of the same drug products and other products that may have been associated with the specific failure or discrepancy. Therefore, a system or an ongoing program should be in place to detect any unplanned deviation per 21CFR211.180(e). If as a result of these activities, changes to conditions established in the application are made beyond the variations that are already provided in that application, the changes must be reported according to 21CFR314.70. Regardless of the need to report changes to an approved application, changes should be managed and implemented per cGMP regulations (e.g.,21CFR211.100 and 21CFR211.22).

These life cycle change management activities are directly linked to successfully implement ICHQ12⁸ for pharmaceutical product lifecycle management, which facilitates the management of post-approval CMC (Chemistry, Manufacturing and Controls) changes in a more predictable and efficient manner. Refer to ICHQ12, pharmaceutical product lifecycle management, for more information.

Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or confirm information about the product and process. The information gathered during the product development and in continued verification stage can be utilized to enable predictable and efficient management of post-approval CMC changes throughout the product lifecycle.

Summary

Process validation is intended to assure the quality, safety and efficacy are designed and built into the drug product through the product lifecycle. It links product and process development knowledge, qualification of the manufacturing process, and ensures the process is maintained in a state of control during commercial production.

Acknowledgment

Thanks for Mahesh Ramanadham, Associate Director for Scientific Operations, Vidya Pai, Branch Chief of DPMIV/OPMA/OPQ, and Ying Zhang, Director of DPMIV/OPMA for providing valuable inputs and editing for this article.

References

1. Guidance for Industry, January 2011 - Process Validation: General Principles and Practices (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices).
2. ICH8 (R2) Pharmaceutical Development, November 2009, (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8r2-pharmaceutical-development).
3. ICH11 Development and Manufacture of Drug Substances (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q11-development-and-manufacture-drug-substances)
4. Q9 Quality Risk Management, November 2012 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9-quality-risk-management)
5. Guidance for Industry, April 2013 - Non-Penicillin and Beta-Lactam Drugs-A cGMP Framework for Preventing Cross-Contamination (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/non-penicillin-beta-lactam-drugs-cgmp-framework-preventing-cross-contamination).
6. Guidance for Industry, October 2004 - Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice)
7. Question and Answers on Current Good Manufacturing Practices - Production and Process Controls (https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practices-production-and-process-controls)
8. Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management- Core Guideline, May 2021 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ich-q12-implementation-considerations-fda-regulated-products)

Author Biography

Rose Xu got her undergraduate degree at the Fudan University School of Medicine. She came to the US to pursue her graduate education, first at Arizona State University, followed by Johns Hopkins University school of Medicine. Rose joined the FDA 12 years ago after spending 10 years in industry. In 2015, she joined the Office of Pharmaceutical Quality (OPQ) to perform both manufacturing process assessment and facility assessment of drug applications including INDs, ANDAs, and NDAs with a variety of dosage forms. Rose is currently Quality Assessment team lead in the office of Pharmaceutical Manufacturing Assessment (OPMA) in OPQ. In addition to the CMC review process, she has also participated in pre-approval inspections of manufacturing facilities (both domestic and international manufacturers), as a subject matter expert, and gained a lot of first-hand field experiences. Rose is an expert on process validation in the OPMA. She is also one of the authors that drafted the guidance to Industry of “Identification of Manufacturing Establishment in Applications Submitted to CBER and CDER, Q & A”.

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