A Basic Guide to Process Validation in the Pharmaceutical Industry

 Validation has become very common word for those who are associated with pharmaceutical industry and now it has been adopted under main quality system and become one of the regulatory requirements.

There are several challenges in pharmaceutical processes, validation is one of that. This is merely due to its scope and complexity. Mere testing of product, even doing several timesand in detail does not provide assurance batch after batch and variations are likely. To ensure the variation within narrow range, control on the process is very essential and to know what to control also sometime emerges from process validation data.

So let us start with official definition of process validation by FDA, “thecollection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product”

Thethree-line definition states a lot because it starts from process design (R&D) stage may be few grams to several kilos of commercial production. Study three words in above definition evaluation of data, scientific evidence.

Let us now evaluate process validation. Quality assurance approach must be covered in each area to get our ultimate aimed consistent quality product.

1.       Process design: Commercial manufacturing process is defined. This is essential to control the same at each stage and if one need to make some changes it must go through pharmaceutical change control process.

2.       Process qualification: This stage evaluates the design stage whether process is capable of re-producibility.

3.       Continued process verification: Ensuring that this process is verified to be in control all the time if processed as per design.

Before proceeding to manufacturing and commercialisation of the process it must be established that product produced meets all the quality standards and manufacturing procedure can accommodate all requirements of safety and efficacy.

The quality of drug substance does not stop at this level only but it must be capable to go to drug product stage withstanding the conversion process. If any variation that may occur during this stage, degree of variation, where occurred and impact of the same must be evaluated. Drug product is recognised by its identity, strength, quality, purity and potency. One must be wondering with these multiple words significance as what can be difference between purity and potency? An optically active compound can also be 100 % pure but may loose its potency if not optically active.

Let us now focus on process because it is the process which will produce the product so its validation is also very important. FDA’s cGMP has defined process validation requirement and some of them are legally enforceable. This means that if any of the requirement specified are not met then the drug product is treated as adulterated.

1.       It must meet all predetermined requirements of processing, packaging and holding.

2.        Control on sampling and testing to represent whole batch and adhere statistical confidence on consistency. Results meet pre-determined specification.

3.       Product quality and manufacturing process must be periodically reviewed and if needed must be adjusted. So continuous review to get feedback on ongoing process is also one of the cGMP requirements.

4.       cGMP also demands not only process but site location, construction and size must meet required needs. Equipment, instruments are inspected and calibrated to get desired performance.

Process design: To determine appropriate process for commercial manufacturing of product. Design experiment should be under sound scientific principles.

Documentation is must hence good documentation practice is essential.

Good practice also suggest continuous testing and re-testing to a condition till process fails (Though not regulatory requirement, it is good for understanding process extreme limits)

Process control and its documentation. In-process control is very essential when the product attribute is not detectable or measurable. (Microbial contamination)

Process qualification: Measure of process design for its capability for commercial production.

1.       Appropriate design, 2. Proper selection of utility and equipment. System and equipment operates within pre-determined criteria.

2.       PPQ (Process performance qualification) to verify whether people, parameters and performance complies.

3.       Written and approved protocol (protocol includes steps methodology, manufacturing condition, control points, in-process control tests) with acceptance criteria.

4.       No activities should be started until the protocol is approved by all concerned including QA

Process Verification: Objective is to ensure that process is always in validated state during commercial production. How do we do that?

1.       Continuous monitoring of data collected as per defined period to monitor product quality.

2.       No variation should occur. If found, immediate action to see effect and take corrective action.

3.       The monitoring and sampling should be at the level which is used at process qualification stage is to be pursued until sufficient data is available to make conclusive analysis.

4.       Maintenance of facility and equipment including calibration should be conducted regularly at defined interval.

Whole above activities should be pursued in order to achieve product quality with safety and effectiveness with better patient care.

Medical device is also for patient care. This product is also used for patient like pharmaceutical product so it also must go all steps of process validation from design stage until commercial manufacturing. Process validation for medical device also more or less follows same steps as pharmaceutical substance.