Start Early

Advanced therapy developers are required to have ancillary materials validation procedures in place that evolve throughout clinical development and up to commercial launch. Research-grade material may be acceptable proof-of-concept studies, but unacceptable for pivotal trials or commercial therapies. A thorough risk assessment is critical to understanding and managing increasing level of compliance.

In our experience, many advanced therapy developers do not adequately consider ancillary material quality at an early enough stage.

Failure to develop your product process and implement high-quality ancillary materials from preclinical or early clinical stages often means that the materials used in early clinical studies are incompatible with late clinical or commercial risk profiles. This can result in an enormous amount of work around qualifying new materials, performing bridging studies, or in some cases even repeating clinical trials.

We Can Help

Akron Biotech offers products at three levels of quality certification: research use only (RUO), pre-clinical grade (manufactured in a cGMP environment), and cGMP grade. Importantly, products at all three levels are similar in biology and function. While pre-clinical grade products are produced under cGMP conditions, they are only qualified to the extent that their intended application requires. Start with RUO and transition to pre-clinical and cGMP grade when you are ready. Our strategy offers your business continuity across the development spectrum, minimizing re-validation work as you scale up.


Stage 1 – Development

Stage 2 – Engineering


SOP/Batch Record

Risk Assessment, Draft

Optimized Draft


Controlled Environment

Sterile Filtration & Aseptic Filling in Class II (100) BSC

Sterile Filtration & Filling in BSC and/or ISO 7 cleanroom with ISO 5

Sterile Filtration & Aseptic Filling in ISO 7 cleanroom with ISO 5 LFH

Accepted Changes

High, in-process and between batches

Minor, in-process and between batches

Minimal, in line with process validations

SOPs in place to control all processes


Yes (in-process)


Run Scale

Pilot Scale

Full Scale

Full Scale to Scale-Up

2ndary Sourcing & SoS


As Necessary



Stage 1 – Development

Stage 2 – Engineering



Certificate of Testing (CoT) with ‘As Reported’ results

Spec suitability of CoT ‘As Reported’ results

Certificate of Analysis (CoA) with specs and acceptance criteria

Safety Testing

One Compendial Method at Minimum, Reported

USP*, Verified

USP*, Validated

Physiochemical Testing
(Appearance, pH, Osmolality et al)

One Compendial Method at Minimum, Reported

USP*, Verified

USP*, Validated

ID & Purity Testing
(HPLC, SDS-PAGE et al)

Developing/Qualified (as applicable)

Qualified/Validated (as applicable)

Validated (as applicable)

Functionality Testing

If Available, Reported



Stability Program

Manuf’g Pilot 3 & 6 months

Begin formal, long-term study

Concurrent long-term study ongoing, accelerated excursion studies


Stage 1 – Development

Stage 2 – Engineering


SOP/Batch Record

Manufacturing Draft

Manufacturing Optimized Draft

QA Approved



Higher Involvement


Approval & Release

Manufacturing & QC

Manufacturing & QC


RM & 3rd Party Testing Supplier Audits


On-site for Critical as required

Planned On-Site Audit Interval for Critical

  • Ancillary materials should be qualified for their source, identity, purity, biological safety, and general suitability
  • There is no single qualification program that suits all ancillary materials; a risk-based approach to material validation must be deployed
  • It is the legal responsibility of the ancillary material user to qualify material quality
  • Working closely with the vendor can substantially reduce the validation workload
  • Once the material has initially been validated for suitability, qualification testing should be performed to assure quality of the material from the manufacturer on an ongoing basis.

Approaches to process validation

Process verification studies should confirm that the final manufacturing process performs effectively in routine manufacture and is able to produce an active substance or intermediate of the desired quality on an appropriate number of consecutive batches produced with the commercial process and scale.9 There are several approaches to process validation, but irrespective of the approach used, processes must be shown to be robust and ensure consistent product quality before any product is released to the market.

  • Traditionally, process validation is performed when product and/or process development has concluded, after scale-up and prior to marketing of the finished product. Some validation studies can be performed on a pilot scale (≥10% of production scale) before commercial scale is reached.
  • Continuous process verification can also be considered, in which process performance is continuously monitored and evaluated. Continuous and traditional approaches can be combined in a hybrid validation approach.
  • Under exceptional circumstances, the validation protocol can be executed concurrently with the commercialization of the validation batches, but this is usually only justified on the basis of significant patient benefit.
  • According to the 2015 GMP guidelines update, retrospective validation is no longer accepted, and all processes must be prospectively validated.

Various practices are considered to develop and validate a manufacturing process.

Process development run: Experimental batches for execution of the process at scale for development of the final manufacturing process, automation, and operation. Development runs are experimental, i.e., not used for clinical or commercial supply manufacturing. This run serves to shake-down the process and equipment, prior to cGMP production.

Engineering run: Full-scale lots of the final process to demonstrate process performance prior to process performance qualification. These may be cGMP for the manufacture of clinical or commercial material. The engineering run serves to shake-down the process and equipment, and confirm acceptable product quality.

Conformance run: Process validation study conducted to confirm that when operated within the established operating ranges, the process performs as expected and with adequate consistency.

Documentation practices

In accordance with GMP guidelines, good documentation practices are essential to support process validation, in addition to the broader product lifecycle. Full guidelines on GMP documentation and records practices can be found in section 6.1 of ICH Q7.7 General guidelines regarding process validation can be found at:

  • EudraLex Vol. 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Humans and Veterinary Use, Annex 15: Qualification and Validation
  • EMA Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission (2016)

Within the process validation procedure, specific documentation practices should be particularly observed:

  • Documentation should be developed that evidences all process validation practices and procedures
  • Thorough documentation is particularly important when managing post-approval change control
  • All documents should be approved and authorized by the appropriate personnel
  • The inter-relationships between documents should be clearly defined
  • Documentation supplied by a third party should be confirmed for suitability and compliance with internal procedures before approval, with additional documentation/tests integrated as necessary

Stability monitoring

An ongoing testing program should be designed to monitor product stability, with the results being used to inform storage conditions and retest/expiration dates.7 Normally, the first three commercial production batches should be placed on the stability monitoring program. However, where data from previous studies shows that the API is expected to remain stable for at least two years, fewer than three batches can be used. Following this, at least one product batch per year should be added to the stability monitoring program. For products with short shelf-lives, testing should be performed more frequently, usually monthly for the first three months, and then at 3-month intervals.

Ancillary materials are often aliquoted or stored at different concentrations or in different conditions to those stated on the label, or compared to previously validated conditions. These alternative storage configurations may be necessarily required by the drug manufacturing process. According to USP <1043>, data should be generated to demonstrate the stability of the ancillary material to the respective application as stored under these conditions.

Clearance strategies for toxins and impurities

In some cases, it may be necessary to use ancillary materials that could present a toxicity risk to the patient, or undermine product safety or efficacy. Potentially toxic impurities include viral vectors, animal-derived products, and some processing reagents. It will be necessary to build in control measures to ensure toxic impurities are not present in the final product to a level that could present unacceptable risk to the patient or product. The first step to controlling for toxic impurities is designing them out of the product process, such as by using clinical-grade ancillary materials, and by qualifying the lack of leachables and extractables from processing plastics. However, it may also be necessary to perform clearance steps to adequately remove toxins from the final product. Several strategies are available to achieve this goal:

  • Serial dilution
  • Nanofiltration
  • Metabolic inactivation
  • Gamma irradiation
  • Chromatography
  • Heat treatment
  • pH treatment
  • Solvent/detergent
  • Ultraviolet radiation

Each method has specific advantages and disadvantages, and may or may not be appropriate for the removal of a particular impurity type. Careful selection and validation of clearance strategies should be performed appropriately.

When testing for impurities which may affect the safety of a product, it is essential to establish the suitability and sensitivity of each test. Two key parameters are of critical importance:

  • Limit of detection (LOD): The smallest measured concentration of an analyte from which it is possible to deduce the presence of the analyte in the test sample with acceptable certainty.
  • Limit of quantification (LOQ): The smallest measured content of an analyte above which the determination can be made with the specified degree of accuracy and precision.

LOD and LOQ are essential metrics when establishing an assays quality and suitability, and should be of adequately low levels so as to ensure the safety of the product with respect to presence of the analyte (such as toxin) that the test is designed to control.

Analytical considerations

When setting a material specification, there are specific analytical considerations to be made. When qualifying an ancillary material or drug product, reference to an international reference standard should be made when calibrating the material specification, if such a standard is available.

For materials without an external reference standard, the manufacturer should establish an appropriately characterized in-house primary reference material, prepared from lots representative of production and clinical materials. In-house working reference materials used in the testing of production lots should be calibrated against this primary reference material.

Analytical procedures used to qualify a material should be validated in accordance with ICH Harmonized Tripartite Guidelines “Validation of Analytical Procedures: Definitions and Terminology” and “Validation of Analytical Procedures: Methodology”, except where there are specific issues for unique tests used for analyzing biotechnological and biological products.10,11