Considerations Regarding Specifications for Allo Therapies

Friday, June 18, 2021

By: Anthony Colenburg - Sr. Director of Quality - Adicet Bio

Introduction

One of the many challenges for startup biotech companies is generating Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring and Available (ALCOA+) supporting DATA in establishing drug substance and drug product specifications. This is no exception for Allogeneic Cell Therapies which fall under the Gene and Cell Therapy umbrella. The European Medicine Agency (EMA) in their International Conference on Harmonization Topic 6 Guidance, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products, defines specification as:

“a list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for tests described.”1

The expectation that is consistent across all manufactured materials is having enough product knowledge that each test acceptance criteria within the specification includes the lot-to-lot variability values generated throughout all identified DATA sources. Of course, this range will be quite large through the early phases of the drug discovery life cycle as DATA from pre-clinical studies tend to be rather variable, but the statistical expectation is that your DATA should fall within three standard deviations above and below the average of each set of test DATA as the product moves through the several phases of development.2

Herein we are presented with the question: what tests, analytical procedures and/or acceptance criteria is considered appropriate for Allogeneic Cell Therapy products? I will provide some industry considerations in this article that will offer insight into developing a plan for your organization.

Definition

Adding to the definition of specification, ICH Q6 reflect that specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities. Specifications establish the set of criteria to which a drug product or materials at other stages of its manufacture should conform to be considered acceptable for its intended use.3 Although a very critical component, specifications are only part of the total control strategy designed to ensure product quality and consistency. Other parts of this strategy include:

  1. thorough product characterization during development;
  2. adherence to good manufacturing practices; and
  3. using a validated manufacturing process, raw materials testing, in-process testing, stability testing, etc.

Principles for Consideration in Setting Specifications4

A.Characterization

Acceptance criteria should be established and justified based on DATA obtained from identified key sources such as lots used in pre-clinical and/or clinical studies, lots used for demonstration of manufacturing consistency (validation runs), stability studies and relevant developmental studies. Testing for biological products consist of:

  1. Physiochemical Properties: heterogeneity (lot-to-lot quality of product) and immunogenicity (safety of product);
  2. Biological Activity: animal-based biological assays, cell culture based biological assays, biochemical assays and potency;
  3. Immunochemical Properties: Enzyme-Linked Immunosorbent Assay (ELISA) & Western Blot; and
  4. Purity, Impurities and Contaminants:
    1. Purity: specific activity (units of biological activity per milligram of product);
    2. Impurities: host cell proteins, host cell DNA (process-related impurities); and
    3. Contaminants: strictly avoided and/or suitable controlled with in-process action limits.
  5. Quantity: protein content.

B. Analytical Considerations5

  1. Reference Standards and Reference Materials: in-house standard, new molecular entities (unlikely standard available); and
  2. Validation of Analytical Procedures: Q2A Validation of Analytical Procedures: Definitions and Terminology3 ; Q2B Validation of Analytical Procedures: Methodology.

C. Process Controls6

  1. Process-Related Considerations: verification at commercial scale, therefore, this concept may be implemented after marketing authorization;
  2. In-Process Acceptance Criteria and Action Limits: tests performed at critical decision-making steps during manufacturing process (show consistency in production); and
  3. Raw Materials and Excipient Specifications: these specifications are established by their manufacturers and passing acceptance criteria values confirmed prior to release and use in manufacturing process.

D. Pharmacopeial Specifications7

  1. Sterility;
  2. Endotoxins;
  3. Microbial Limits;
  4. Volume in Container;
  5. Uniformity of dosage units; and
  6. Particulate Matter.

E. Release Limits Versus Shelf Life Limits

Release limits should be tighter than shelf-life limits, where applicable.

F. Statistical Concepts

There is an array of statistical options that can be used to analyze and quantitate your DATA. Chosen methods should be used consistently across all lots used to establish acceptance criteria.

Justification of Specifications8

All principles identified for considering specifications A-F in the previous section are used themselves to justify the specifications. The DATA generated IS your verification. The sequential approach of this control strategy include:

  1. Raw materials and excipients;
  2. In-process testing;
  3. Process evaluation or validation;
  4. Adherence to current Good Manufacturing Practices;
  5. Stability testing; and
  6. Testing for consistency of lots.

Considerations when establishing scientifically justifiable specifications:9

  1. Base your specifications on DATA obtained from lots used to demonstrate manufacturing consistency;
  2. Propose a stability-indicating profile – changes in the quality of the product will be detected (ICH Q5C Stability Testing of Biotechnology/Biological Products);
  3. Based on DATA obtained from lots used in pre-clinical and clinical studies;
  4. Critical Quality Attributes (CQAs) may include Potency, Quantity of product-related substances, product-related impurities, and process-related impurities; and
  5. Selection of tests to be included are product-specific and rationale used to establish acceptable ranges. 

ICH also address separately Gene and Cell Therapy products (which includes Allogeneic products) and considerations around generating specifications. The following reflect Industry’s current thinking:10 

ICH Q6A – cGMP for Phase I Investigational Drug 

Gene Therapy and Cellular Therapy Products

  1. Manufacturers should consider the appropriateness of additional or specialized controls;
  2. Include justification for adopting additional controls or alternative approaches to FDA recommendations;
  3. Manufacture of multiple batches – accumulate DATA;
  4. Monitor manufacturing performance to ensure product safety and quality; and
  5. Manufacturer’s periodically conduct and document internal performance reviews of manufacturing process to assess if process is optimal to ensure overall product quality:
  6. Appropriate modifications and Corrective Actions can be taken to control process.a

Special Manufacturing Situations – Biological and Biotechnological Products [Allogeneic Therapies]

Phase 1 Clinical Trials: complete knowledge and under-standing is limited; comprehensive product characterization is often unavailable. As progression occurs during the drug development lifecycle, product knowledge and understanding increases exponentially making specification development more and more achievable

With the information provided thus far, a Specification platform or template can be generated using universal tests covering Safety, Identification, Strength, Quality, Potency/Purity (SISQP):

  1. Appearance & Description: A qualitative statement of the physical state (e.g., solid, liquid), color and clarity.
  2. Identity: Highly specific & based on unique aspects of its molecular structure and other specific properties.
  3. Assay: A specific, stability-indicating procedure to determine strength (content) should be included.
  4. Purity & Impurities:
    1. Method dependent and purity is estimated by a combination of methods.
    2. Process-related impurities may include cell culture media, host cell proteins, DNA, monoclonal antibodies or other.
    3. Product-related impurities are molecular variants with properties different from those of the desired product.
  5. Potency:
    1. Validated potency assay while an alternative physiochemical and/or biological may suffice for quantitative assessment (specific activity may provide some additional useful information).
    2. Organic and inorganic impurities (degradable products) and residual solvents are included.

  6. Quantity: usually based on protein count (mass) and should be determined using an appropriate assay.

Due to proprietary reasons, I am unable to provide an actual product specification, however, ICH Q6B provides an example specification template of a monoclonal antibody (mAb) drug substance that reflects all aspects of associated testing and acceptance criteria in a similar fashion as an allogeneic drug product specification, considering what we discussed in this article.11

Summary

Startup biotech companies, including those manufacturing Allogeneic Cell Therapies, can overcome the challenge of establishing drug substance and drug product specifications by ensuring all supporting DATA are Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring and Available (ALCOA+). Product knowledge is key from being aware of lot-to-lot variability to understanding as the drug progresses through the early to late phases of the drug discovery life cycle, three standard deviations above and below the average of each set of tests will be the main focus in developing acceptance criteria.

In conclusion, specification acceptance criteria and associated compiled DATA should be monitored for opportunities to continuously improve the manufacturing process. Quality Management Review should identify these areas of possibilities, however, just because an opportunity for improvement is presented (i.e., reduction/tightening of acceptance limits) doesn’t necessarily mean it should always be taken. Internal discussion and a path forward should be agreed to by all parties. Otherwise, the opportunities can continue to be viewed as product knowledge.

References

  1. ICH Q6A. 1999. Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. Current Step 4 version dated 06 October 1999.
  2. ICH Q8(R2). 2009. Pharmaceutical Development. Current Step 4 version dated August 2009.
  3. Colenburg A. 2021. BioProcess International US West Virtual Conference. “Considerations Around Specifications for Allogeneic Therapies”.
  4. ICH Q10. 2008. Pharmaceutical Quality System. Current Step 4 version dated 04 June 2008.
  5. ICH M3(R2). 2009. Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Current Step 4 version dated 11 June 2009.
  6. ICH Q3A (R2). 2006. Impurities in New Drug Substances. Current Step 4 version dated 25 October 2006.
  7. ICH Q3B(R2). 2006. Impurities in New Drug Products. Current Step 4 version dated 02 June 2006.
  8. EMA. 2011. Report on the expert workshop on setting specifications for biotech products, European Medicines Agency, London, 09 September, 2011. EMA/CHMP/30584/2012.
  9. Tsang PKS, Larew JSA, et al. 1998. Statistical approaches to determine analytical variability and specifications: Application of experimental design and variance component analysis. J. Pharm. Biomed. Anal., 16, 1125-1141.
  10. Ermer J. 2001. Validation in pharmaceutical analysis. Part I: An integrated approach. L. Pharm. Biomed. Anal., 24, 755-767.
  11. Moran E, Perry M. 2011. Setting specifications, statistical considerations. EuropaBio Meeting. http://www.ema.europa.eu/docs/en_GB/document_library/ Presentation/2011/10/WC500115818.pdf. Accessed on 12th May 2021.

Author Biography

Anthony Colenburg, Sr. is the Director of Quality for Adicet Bio, a biotechnology company engaged in the development of first-in-class off-the-shelf allogeneic gamma delta T cell therapies for cancer and other diseases. Anthony has worked in every phase of drug development from research & development, through early and late phase clinical trials to commercial marketed drug products worldwide. Anthony also is a Life Science Industry speaker who conveys to organizations within his audience around the globe the importance and criticality of having and applying a phase-appropriate approach to Quality Systems. Lack of this approach has proven to be critical on many occasions as regulatory agencies will scrutinize quite heavily organizations that attempt to jump full throttle from the gate without having a phased approach to Quality Systems which oversee their drug discovery life cycle. His area of expertise covers Quality by Design (QbD), data Integrity establishment and management, process design & simplification through lean and continuous improvement initiatives, collaborative quality culture development, proven QA on-the-floor manufacturing and operations efficiency gains and team building. Prior to working at Adicet Bio, Anthony worked throughout industry specifically with contract development manufacturing organizations and testing laboratories improving their Quality Operations and many elements of Quality Systems.

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