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Ask the Expert

Joseph A. Albanese, director of Analytical Strategy and Compliance at Janssen Research and Development, LLC

Gail Reed is senior scientist with Johnson & Johnson.

Yelena Ionova is senior manager, Data Strategy and Analytics with Redica Systems.

J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions LLC.

A businessman pointing at a compliance icon with a technological business data network in the background, representing regulatory standards | Image Credit: ©AhmadTriwahyuutomo - stock.adobe.com

A specification is defined by the International Council for Harmonisation (ICH) documents Q6A and Q6B (1,2) as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. A specification establishes the set of attributes and their associated criteria to which an excipient, drug substance or drug product should conform to be considered acceptable for its intended use. Conformance to specifications means that the excipient, drug substance, and/or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. The guidance documents go on to indicate that specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. Specifications are foundational to a robust control strategy for all components of a finished dosage form.

Many bio/pharmaceutical companies find themselves trying to meet specifications for an excipient, drug substance and drug product that may have different tests and acceptance criteria in different regions or countries around the world. Companies can establish scientific rationale that methods are equivalent for a specific attribute (test) on the material’s specification, and then when tested, the material will comply with the acceptance criteria for all applicable regions. This risk-based approach is often used by companies to reduce the testing burden for release and stability laboratories. However, companies struggle with establishing equivalence for different methods used for the same attribute on the specification. Oftentimes, the acceptance criteria for the methods are not suitably considered in the evaluation.

As an example, pharmaceutical manufacturers often try to determine specification equivalence for materials that come from different sources. The different sources could be the “same” material produced at two or more sites or made by two or more suppliers. While the comparison of specifications may appear to be a straightforward exercise, the details of the differences for both the analytical procedures and the acceptance criteria make the determination far more complicated. Specification equivalence is essential to determining if two different analytical procedures produce the same results for a given substance or product regardless of the manufacturing site. Specification equivalence is the first step in assessing the potential differences for materials from different sources. Once the analytical assessment is completed; a manufacturing assessment may also be required.

This series of papers intends to offer a practical approach to the concept of specification equivalence, first defining key terms used in the specification evaluation process in this paper. Subsequent papers will take a deeper dive into method equivalence and acceptance criteria equivalence which results in a process leading to a scientific decision on specification equivalence for a given attribute on a material specification. The last paper of the series will focus on the steps needed to perform specification equivalence for compendial materials where the respective monographs in the world’s pharmacopeia may not be harmonized.

Advances in technology, new regulatory requirements, and manufacturing processing changes are some of the potential reasons that there is a change to an analytical procedure or to the associated acceptance criteria. It is recognized by the health authorities that changes will occur in the lifetime of a material/product and there are pathways to make these changes with the impacted regulatory agencies. These pathways require suitable documentation to demonstrate that the changes being made continue to ensure suitable quality pharmaceutical substances and products for the patients. It also can provide a business opportunity to “harmonize specifications” and minimize redundant testing especially for multi-market products.

Specification equivalence can be defined in a way that is generally consistent with that of method equivalence published by Chambers (3) but is more fundamentally based upon the Pharmacopoeial Discussion Group (PDG) definition for harmonization, which is when a pharmaceutical substance or product tested by the harmonized procedure yields the same results and the same accept/reject decision is reached (4). The authors believe that adapting the PDG definition to include non-compendial methods provides for the most straightforward approach to determine specification equivalence. Additionally, specification equivalence draws on the concept of “harmonization by attribute”, which is an approach established by the PDG when an entire monograph (i.e., specification for a material) could not be harmonized. The PDG focused on the individual attributes that could be harmonized. The same is true for specification equivalence. Companies can go attribute by attribute to do a risk assessment of the methods and their acceptance criteria to ensure the same accept/reject decision is reached. Specification Equivalence is illustrated in 

. The benefit of re-defining this approach for specification equivalence is to minimize the use of cumbersome statistical techniques that can confound the analysis and to bring more emphasis to the acceptance criteria for the specific attribute.

Figure 1. Specification Equivalence by Attribute. (Figure courtesy of the authors)

The challenge of determining equivalency lies in the components of the specification, namely the analytical procedures and the acceptance criterion for the method. The differences encountered in both analytical procedures and the acceptance criterion can rapidly confound a straightforward approach to determine equivalency. In this series of papers, the authors examine all the parts of a specification and the role each plays in determining specification equivalence. The authors will offer a streamlined process to achieve a decision on specification equivalence, including a simple flow chart assessment for both the analytical procedure and its associated acceptance criteria. These flow charts could be used in a manufacturer’s Standard Operating Procedure (SOP) or Guidance for Specification Equivalence established by a bio/pharmaceutical manufacturer.

Both small-molecule and biotherapeutic drug products are in scope of the paper, and the approach applies to release and shelf-life (where applicable) specifications for excipients, drug substances, drug products, and primary packaging containers used by pharmaceutical manufacturers. Microbiological methods are out of scope for this series of papers.

In essence, the authors provide an approach to perform “in-house harmonization” of specifications, or introduction of new methodology, assessing each method and associated acceptance criteria to provide scientific justification that will allow a company to comply with health authority regulations. Therein lies the connection with the PDG concept of harmonization, namely, the same accept/reject decision would be reached regardless of the analytical method employed for that material.

The detailed impacted analytical procedures, associated acceptance criteria, relevant validation packages or method verification packages, method transfers as well as any other generally known information about the methods and then the impacted materials or products must be collected. Each of the two or more methods must first be suitably validated to the current standards described by regulators. It is crucial that the validation package is reviewed for any gaps to current standards; this becomes especially relevant for analytical procedures that were not recently validated or gap assessed. Additionally, if one method was developed and validated by a different laboratory, it is required that the receiving laboratory properly demonstrate it has implemented the method as it was intended to be run (i.e., method verification or transfer). With the two methods suitably validated and verified in a laboratory, it is possible to determine if the methods are comparable or equivalent. Layering in the acceptance criteria associated with each method, it is possible to determine specification equivalence.

As the paper expands on these concepts for assessing specification equivalence, it is important to keep in mind the terms used for analytical methods and their relationship to specification equivalence: method validation, method verification, method comparability and method equivalence. These terms can be confused and have been wrongly used by manufacturers to describe work they have completed. Method validation and method verification have been the subject of confusion. With the adoption of ICH Q2(R2) (5), ICH Q14 (6), and several general chapters in the pharmacopeia (e.g., 

] <1225> and <1226>) some clarity has been provided to industry. The ICH guidance documents will be addressed in a subsequent paper in the series.

Specification equivalence: regulatory guidance

There is not a lot of regulatory guidance provided on the topic of specification equivalence. For analytical procedures, the first part of a specification, there is some guidance provided by the pharmacopoeia. All pharmacopoeias allow, via their General Notices, for the use of “alternative methods” when testing a substance or product by an existing monograph. Use of an alternative method entails risk because of the associated regulatory restrictions of using an alternative method. Specifically in Europe, the 

. General Notices clearly indicate that approval of the competent authority is needed prior to using an alternative method for routine testing. Not receiving this approval places a bio/pharmaceutical manufacturer in a position of non-compliance. Additionally, most global pharmacopoeia General Notices sections include a disclaimer “that in event of doubt or dispute, the analytical procedures of the pharmacopoeia are alone authoritative.” This means that if the alternative method provides a different result than the pharmacopoeia method, the result obtained by the pharmacopoeia method is viewed as the official result.

. has published a first of its kind general chapter, 5.27 Comparability of Alternative Analytical Procedures, which is an informational chapter that became official July 2024. (7) This general chapter’s intent is to provide information to help manufacturers demonstrate that an alternative method is comparable to a pharmacopoeial method. It is stressed in the preamble of the chapter that, “The use of an alternative procedure is subject to authorization by the competent authority. The final responsibility for the demonstration of comparability lies with the user and the successful outcome of the process needs to be demonstrated and documented to the satisfaction of the competent authority” (7). The burden (or risk) of demonstrating comparability is on the manufacturer. However, these requirements are mainly focused on the validation state of the alternative method because pharmacopoeial methods are considered validated to current requirements. After the methods are determined to be of suitable validation status, the chapter indicates that a study where the same samples are tested by both methods should show that the results of the alternative procedure lead to the same unequivocal decision that would be made with the pharmacopoeial procedure. The chapter provides a visual reference of statistical assumptions that should be considered in the data analysis.

FDA issued a draft guidance in July 2015 entitled 

Analytical Procedures and Methods Validation for Drugs and Biologics–Guidance for Indu

stry (8). This guidance is mostly focused on validation parameters of a method and there is a section focused on the use of alternative methods. The information is consistent with the requirements provided by the pharmacopoeia to demonstrate that one method is comparable to another. However, there is no specific guidance provided on method equivalence (i.e., that the same accept/reject decision would result when tested by either method).

Specifications component: analytical procedures

Looking first at the analytical procedures included in the specifications; there are clear requirements from regulators and pharmacopoeias that the analytical procedures are validated and/or verified.

Method validation is the evaluation of the analytical procedure performance characteristics (APPCs) such as specificity/selectivity, sensitivity (at the lower range limit), accuracy, linearity, and range. All these characteristics should be assessed to ensure the method meets the requirements expressed in ICH Q2 (5). These same requirements are also clearly described in section VI B of the FDA guidance referenced previously, which provides more detail on verification activities for non-compendial methods in the same section (8).

Method verification is the assessment of whether the analytical procedure can be used for its intended purpose, under the actual conditions for use for a specified material. Methods must be demonstrated to be suitable for use and applicable under actual conditions of use in the implementing laboratory. A US regulation in the Federal Food, Drug, and Cosmetic Act (FD&C Act) code speaks directly to method verification, namely 21 

) 211.194(a)(2), which states, “suitability of all testing methods used shall be verified under actual conditions of use” (9). The FDA guidance on 

Analytical Procedures and Methods Validation

 provides more detail on verification activities for a compendial method in Section VI, C. (8).

General Chapter 5.26, Implementation of Pharmacopoeial Procedures in the 

 (10) indicates that the implementation of a compendial procedure in a laboratory is a combination of the implementation assessment and the verification assessment. The implementation assessment evaluates if there are any factors associated with the complexity of the procedure and the actual conditions of its use in the implementing laboratory that may affect the performance of the procedure. If any factors are determined to potentially affect the successful implementation, then a verification assessment must be completed. The verification assessment is laboratory work performed to ensure that the procedure is suitable for examination of the article under test, under the actual conditions of use. If the implementation assessment identifies the need for verification experiments, relevant analytical procedure performance characteristics (APPCs) are assessed and verified depending on the intended use of the analytical procedure. A convenient guide is provided for manufacturers to consider when performing verification experiments. Lastly, the general chapter states that these activities should be captured in an appropriate quality system. The requirements to document this activity will be discussed in a subsequent paper in this series.

It should be noted that method validation and method verification activities are carried out for a specific analytical procedure. If multiple analytical procedures are under consideration, the user must ensure that each procedure is validated and verified (if needed). Method validation and method verification are scientific and compliance activities that need to be completed for each of the separate analytical procedures under evaluation as shown in 

. The completion of these two activities for each analytical procedure is necessary before an equivalence study can be undertaken. On the other hand, method comparability and equivalence involve the evaluation of the method validation work completed across multiple analytical procedures as shown in 

Figure 2. Method A’s Validation and Verification are INDEPENDENT of Method B’s Validation and Verification. (Figure courtesy of the authors)

, (3) define method comparability as studies to evaluate similarities and differences in method performance characteristics between two analytical methods (i.e., accuracy, precision, specificity, detection limit, and quantitation limit). In other words, comparability is an evaluation of the method validation results for each method. The comparison of their performance characteristics allows a determination as to whether there are any method limitations or lack of sufficient capability (e.g., limit of quantitation [LOQ] is too high for one method; critical pairs of impurities are not separated, etc.). Determination of differences in the performance characteristics of the methods is important to help identify whether one method is superior to another method but does not allow one to say whether or not the methods can generate equivalent results. That can only be accomplished with a method equivalence evaluation.

Figure 3. Method A directly compared to Method B evaluating differences in Analytical Procedure Performance Characteristics. (Figure courtesy of the authors)

, (3) define method equivalence as studies to evaluate similarities between two analytical procedures regarding generating results for the same sample. In other words, analytical method equivalency evaluates whether the new method can generate equivalent results to those from an existing method. The concepts of comparability and equivalence between analytical methods are illustrated in 

, which shows the applicability across multiple procedures, rather than for one specific procedure. Method equivalence is used to identify the level of risk for not running every method for every test required by every country. In performing method equivalence, understanding the acceptance criteria in relation to the different procedure’s capability is an important consideration to reaching a sound scientific conclusion.

Specifications component: acceptance criteria

Appropriate acceptance criteria are established for a specific pharmaceutical substance or product based on manufacturing capabilities and quality considerations. The acceptance criteria are applicable to the specific analytical procedure used in the determination of material acceptability and within regulatory commitments. When considering different acceptance criteria for different methods, a well-accepted practice is to apply the tightest limits. Choosing the tightest acceptance criteria is a straightforward choice, ensuring that if the result obtained from an analysis meets the criterion, it will comply with all acceptance criteria established for all markets. Readers should be cautioned to ensure that the tightest acceptance criteria make scientific sense and are consistent with the manufacturing process capability for the substance or product and are within the analytical method capability for the substance or product.

However, choosing the tightest limits may not always be possible. If an analytical procedure has a one-sided limit and the second analytical procedure that will be compared to the first procedure has a two-sided limit, using the upper or lower boundary of the one-sided limit may not be practical or scientifically sound.

Method equivalence helps assess the risk of not performing every method for every test required by every country. By trying to do this risk assessment, as mentioned earlier, it is a prerequisite that the user of the analytical procedure ensure that both methods are suitably validated and verified before any method equivalence study is conducted.

The importance of performing method verification, method comparability, and method equivalence cannot be overstated. Failure to adhere to the regulations outlined in 21 

 part 211 has resulted in numerous citations by the regulatory authorities. Since 2010, 21 

211.194(a)(2), which mandates the verification of all testing methods under actual condition of use, has been cited in 155 distinct inspections. Of these, 45 led to Official Action Indicated (OAI) classifications (29%), and 20 escalated to warning letters (12.9%). US 21 

211.165(e), which requires that the accuracy, sensitivity, specificity, and reproducibility of test methods be established and documented in accordance with 211.194(a)(2), has been cited more frequently during the same time frame, appearing in 488 inspections, leading to 131 OAI classifications (26.8%) and 69 warning letters (14.1%) (see 

) (11). Since 2010, the average rates of OAI and Warning Letter issuance associated with any 21 

 Part 211 citation have been 26% and 13.9%, respectively, indicating that inspections citing 21 

211.194(a)(2) are slightly more likely to result in an OAI classification compared to the overall average for 21 

Deficiencies outlined in these warning letters signal critical compliance failures. For instance, DuPont Nutrition USA received a warning letter from FDA (12) in December 2022 after failing to validate and verify its compendial and non-compendial methods for conductivity testing of Avicel, a widely used microcrystalline cellulose excipient. The third deficiency cited in the warning letter underscores the failure to ensure that the test methods used for in-process and release testing were suitable for their intended use. Specifically, the company did not adequately verify its compendial conductivity test method or validate its non-compendial method. Notable deficiencies included the absence of an approved verification protocol, failure to evaluate the accuracy of the method, and a lack of scientific rationale to support the range evaluated during the method verification (i.e., the acceptance criteria were not considered during the company’s evaluation). Additionally, the non-compendial method used for in-process and packaging testing showed a low correlation with the compendial method. Despite this, DuPont released the excipient that failed to meet USP conductivity standards.

In July 2023, Intas Pharmaceuticals Limited received a warning letter from FDA (13) citing critical violations that directly relate to 21 

 211.165(e). One of the key deficiencies noted was the company’s failure to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods. Specifically, Intas did not perform necessary method validation or verification for multiple in-house and compendial methods used in testing of critical raw materials.

Analytical laboratories that perform testing for drug manufacturing facilities are subject to similar regulatory oversight as drug manufacturers. For example, Valisure, a contract analytical lab facility, received a Form 483 from FDA (14) in 2021 for failing to adequately validate and verify several analytical methods used in the testing of pharmaceutical products. Specifically, the firm was cited for failing to document the validation and verification process, establish acceptance criteria, or evaluate the validity of the methods for their intended use. The observation also noted that “the firm failed to verify equivalency” between methods. Following the issuance of the Form 483, Valisure received an untitled letter from FDA in December 2022 (15), which further underscored deficiencies in method validation processes. While Valisure’s testing may not be used for regulatory purposes, FDA expressed concern that the drug manufacturing facilities would use their test results for current good manufacturing practice (CGMP) purposes. This highlights the broader regulatory expectation that both drug manufacturers and contract laboratories must adhere to the validation and verification standards to ensure drug quality.

Similar deficiencies were identified in a FDA Form 483 issued to Hikma Pharmaceuticals USA in June 2024 (16), highlighting issues related to method comparability under 21 

 211.160(b). This regulation requires that laboratory controls include scientifically sound and appropriate test procedures to ensure that drug products conform to established standards of identity, strength, quality, and purity. Regulators cited Hikma for failing to include established key characteristics of method validation, such as accuracy and instrument comparability, in their co-validation process. In addition, the co-validation of the analytical procedure was conducted at Hikma’s Research and Development laboratory, while the original validation was performed by their contracted testing laboratory. Neither validation included justification for excluding key characteristics beyond precision.

 211.165(e) citations since 2010. (Table courtesy of the authors)

Demonstrating specification equivalency appears to be a straightforward task but can be quite complex for bio/pharmaceutical companies to consistently complete. In this paper, several important terms were defined that will be the foundation of additional papers to follow providing a practical approach to specification equivalence. The regulatory risk of not doing appropriate specification equivalency was also demonstrated with recent trending of FDA inspection data. The rate of these observations indicates that more direction for the regulatory expectations is needed for industry. There are some regulatory and pharmacopeial guidance documents available, but the documents remain at a high level in their detail and their approaches. The coming papers will provide an in-depth breakdown on analytical method equivalence, acceptance criteria equivalence, and a process for completing in-house specification equivalence to help eliminate duplicate or redundant testing in laboratories. The next paper in this series will give the bio/pharmaceutical companies decision trees to help determine method equivalence and acceptance criteria equivalence and a process for in-house specification equivalence that could serve as a basis for company’s SOPs.

Specifications: Test Procedures and Acceptance Criteria For New Drug Substances And New Drug Products: Chemical Substances

https://database.ich.org/sites/default/files/Q6A%20Guideline.pdf

Specifications: Test Procedures and Acceptance Criteria for Biotechnological/ Biological Products

https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf

Chambers, D.; Kelly, G.; Limentani, G.; Lister, A.; Lung, K.R.; Warner, E. Analytical Method Equivalency, An Acceptable Analytical Practice, 

Evaluation And Recommendation Of Pharmacopoeial Texts For Use In The ICH Regions

https://database.ich.org/sites/default/files/ICH_Q4B%28R1%29_Guideline_2024_0605.pdf

ICH. Q2 Validation of Analytical Procedures Q2(R2) (ICH, November 2023). 

https://database.ich.org/sites/default/files/ICH_Q2%28R2%29_Guideline_2023_1130.pdf

https://database.ich.org/sites/default/files/ICH_Q14_Guideline_2023_1116_1.pdf

EDQM. General Chapter 5.27 Comparability of Alternative Analytical Procedures. 

Guidance for Industry–Analytical Procedures and Methods Validation for Drugs and Biologics

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/analytical-procedures-and-methods-validation-drugs-and-biologics

General Chapter 5.26 Implementation of Pharmacopoeial Procedures. 

Redica Systems (2024). FDA Citations [Data sourced from Freedom of Information Act (FOIA) responses and the FDA Inspections Citations Details table at 

https://datadashboard.fda.gov/ora/cd/inspections.htm

FDA. Warning Letter to DuPont Nutrition USA Inc. Dec. 2, 2022. 

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/dupont-nutrition-usa-inc-627211-12022022

FDA. Warning Letter to Intas Pharmaceuticals Limited. Nov. 21, 2023, 

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/intas-pharmaceuticals-limited-662868-11212023

Redica Systems. Valisure, LLC–Form 483, 2021-07-06, 

https://redica.com/document-store/documents/view/100102186/valisure-llc-form-483-2021-07-06

FDA. Valisure LLC, New Haven, CT 12.5.22 Untitled Letter. FEI 3012063246, 

https://www.fda.gov/media/163682/download

FDA. Hikma Pharmaceuticals USA Inc. Cherry Hill, NJ. 483 issued 06/12/2024. 

https://www.fda.gov/media/179799/download

Joseph A. Albanese is the managing director and consultant with Albanese Consulting, LLC. Gail Reed is senior scientist with Johnson & Johnson. Yelena Ionova is senior manager, Data Strategy and Analytics with Redica Systems. J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions, LLC.

Articles

In this first of a four-part series, the authors provide an introduction to a practical approach for establishing specification equivalence.  The regulatory basis and compliance examples from FDA observations and warning letters are included to support the need for an effective process.

Specification Equivalence—A Practical Approach

Industry Outlook for 2025—Real World Data

The use of real-world data (RWD) and real-world evidence (RWE) has become a focus of pharmaceutical regulators in recent years. In December 2024, FDA’s Center for Drug Evaluation and Research announced a new Center for Real-World Evidence Innovation that will coordinate and promote the use of these data in regulatory decision making (1). The agency also published a number of guidance documents on data in 2023 and 2024 (2,3). The European Medicines Agency is also working to promote the use of RWD and RWE (4).

To gain more perspective on these data and other trends impacting the industry, 

® spoke with Sujay Jadhav, CEO of Verana Health. “We're seeing exponential changes in both of those particular components,” says Jadhav. “[F]rom an approach perspective, particularly in clinical research, we're seeing sort of external control arms becoming more mainstream. Part of [this is because] of [FDA] and their guidance of late, which [is about] helping facilitate the leveraging of real-world data and external control arms in the overall drug discovery process. But a key component is that this is an incredible source to help improve sort of efficiency and the quality of our research overall.”

“One of the other trends that we are also seeing is predictive analytics and AI [artificial intelligence], and how this can help predict disease progression and assist with early detection to support patient recruitment and retention … AI and these technologies, they can identify trends for data, [and lead to] informed decisions across the drug life cycle.”

Click the above video to watch the interview.

1. Haigney, S. FDA Creates CDER Center for Real-World Evidence Innovation. 

Guidance for Industry, Data Standards for Drug and Biological Product Submissions Containing Real-World Data

Guidance for Industry, Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products

 (CDER, CBER, July 2024).
4. Barton, C. Using RWD in Non-Interventional Studies. 

Videos

Pharmaceutical Technology® spoke with Sujay Jadhav, CEO of Verana Health about trends in real-world data and the impact these trends will continue to have on the pharmaceutical industry in 2025.

Industry Outlook for 2025—Real-World Data

Feliza Mirasol is the science editor for 

FDA announced on Dec. 23, 2024 that it has approved Hikma Pharmaceuticals USA’s liraglutide injection, the first generic referencing Victoza (liraglutide injection) 18 mg/3 mL from Novo Nordisk. Liraglutide injection is a glucagon-like peptide-1 (GLP-1) receptor agonist. Hikma Pharmaceuticals’ generic version is indicated for improving glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes as an adjunct to diet and exercise.

There is currently a drug shortage of liraglutide injection and certain other GLP-1 medications, according to FDA in a press release (1). The agency is thus prioritizing assessment of generic-drug applications for drugs in shortage to help improve patient access to these medications.

“[FDA] supports development of complex generic drugs, such as GLP-1s, by funding research and informing industry through guidance as part of our ongoing efforts to increase access to needed medications,” said Iilun Murphy, MD, director of the Office of Generic Drugs in FDA’s Center for Drug Evaluation and Research, in the press release (1). "Generic drugs provide additional treatment options which are generally more affordable for patients. Today’s approval underscores [FDA’s] continued commitment to advancing patient access to safe, effective, and high-quality generic drug products.”

Liraglutide improves blood sugar levels by having similar effects in the body as GLP-1 in the pancreas. There are often insufficient levels of GLP-1 in type 2 diabetes patients. More than 38 million people in the United States have diabetes, and 90% to 95% of those individuals have type 2 diabetes, according to the Centers for Disease Control and Prevention (1).

FDA, meanwhile, has been addressing challenges related to the development of generics and the promotion of more generic competition. Addressing these challenges is a key part of the agency’s Drug Competition Action Plan and its efforts to help increase patient access to medicines.

The development of complex drug products such as liraglutide can be even more difficult because of their complex active ingredient, formulation, or mode of delivery. For these reasons, many complex drugs lack generic competition. Thus, to address this issue and enable timely development and approval of needed medications, especially complex products, FDA has been working to clarify regulatory expectations for applicants early in the development process, which includes the agency’s guidances for industry and the pre-abbreviated new drug application program. “These efforts make it more feasible for manufacturers to develop generic drugs and can enhance patient access to treatment by helping make these products more available, allowing patients in the United States to obtain the medicines they need,” FDA stated in its press release (1).

FDA had earlier approved the first generic in this class of medications in November 2024, when it approved a generic referencing Byetta (exenatide). The approval for the generic exenatide 1.2 mL and 2.4 mL prefilled pen injection was granted to Amneal Pharmaceuticals (2).

1. FDA. FDA Approves First Generic of Once-Daily GLP-1 Injection to Lower Blood Sugar in Patients with Type 2 Diabetes. Press Release. Dec. 23, 2024.
2. Amneal Pharmaceuticals. Amneal Resubmits DHE Autoinjector New Drug Application and Receives U.S. FDA Approval of Exenatide, its First Generic Injectable GLP-1 Agonist. Press Release. Nov. 21, 2024.

FDA's approval of Hikma Pharmaceuticals’ liraglutide injection makes this product the first generic version of Victoza, a GLP-1 receptor agonist.

First Generic of a GLP-1 Injection Gets FDA Nod to Treat Type 2 Diabetes

Margaret Radford is unlicensed medicine services manager at Almac Clinical Services.

Lyn McNeill is Just in Time Manufacturing Solutions manager at Almac Clinical Services.

supply chain management concept, procurement, warehousing, transportation, distribution - vector illustration | Image Credit: ©j-mel – stock.adobe.com

In the era of patient centricity, managed access programs (MAPs) are coming of age. While this program type was previously considered a more reactive tactic, sponsors today are increasingly harnessing MAPs—also known as compassionate use programs or early access programs—to provide patients with an unmet medical need with access to unlicensed medication. Used as a strategic tool, MAPs can facilitate optimized, patient-centric, and cost-effective access to investigational drugs outside of a trial setting.

As use of MAPs matures, the potential they represent is becoming more universally acknowledged. As MAPs are designed to deliver treatment access, rather than facilitate research and commercialization, they can be simpler and more cost-effective to operate. MAPs can also support the expansion of patient demographics, strengthen relationships with patient advocacy groups, increase exposure to more healthcare professionals prior to commercialization, and support corporate social responsibility agendas.

There are, however, several key challenges that can prevent sponsors realizing the full potential of MAPs. Many of which can be overcome by embracing a just-in-time manufacturing (JTM) strategy.

Specific challenges vary depending upon the pathway chosen (named patient or patient cohort) but relate to regulatory oversight, product presentation, and supply chain.

Where regulatory activity is concerned, a patient cohort pathway will place full responsibility on the sponsor. This pathway can increase the burden of operating a MAP, especially in regions like Europe, where each member state has its own legislation relating to how European Medicines Agency recommendations are implemented.

Likewise, the nuanced supply chain challenges relating to MAPs are significant. Due to the reactive nature of the program type, demand forecasting is particularly difficult. This difficulty increases the risk of waste or rework if supplies surpass expiry dates while awaiting patient allocation, which can be particularly costly when dealing with biologics and advanced therapies. It also increases the risk of negative patient impact if insufficient drug is available when the patient need arises. In either scenario, a sponsor’s ability to start-up and respond quickly once demand is known is seriously hindered.

To overcome these challenges, the industry is seeking better solutions for MAPs delivery. Solutions that deliver an improved service to patients and healthcare providers (HCPs), while driving improved operational efficiency. JTM is proving useful in this respect by increasing flexibility for packaging and labeling to meet both geographical and forecasting complexities and providing sponsors with more effective management of supplies across both MAPs and clinical trials.

JTM refers to the late-stage customization of clinical kits. It’s a demand-led production technique designed to put patients first and deliver an adaptive supply strategy to meet expanding challenges, including concurrent clinical trial and MAP delivery. JTM achieves all this by delaying secondary packaging and labeling activity until patient or site need arises.

And it really comes into its own where MAPs are concerned. For instance, late-stage customization means unlicensed medicines can be directed to where they are needed, both in terms of geography and volume, helping to reduce cost by conserving drugs. Supply also becomes more flexible when using JTM, as supplies can be used for any country without the need for booklet labels.

Similarly, JTM supports supply pooling, empowering sponsors to use the same bulk supply across clinical trials and MAPs and, through standardizing key elements across pooled lots, benefit from economies of scale without sacrificing the flexibility required to share the product. And because products are only packaged and labeled when needed, JTM reduces exposure to expiry date events. Not only is there less date labeled stock at risk of expiry update loss in the field, but there is also no depot stock requiring relabeling.

Where patient centricity is concerned, JTM supports MAP sponsors to deliver patient specific packaging, helping to lower overheads and improve patient understanding and compliance.

MAPs are typically subject to significant change. Timelines can shift. Participating countries can alter. Regulation and ongoing clinical trial activity can influence supply requirements. While operating a traditional batch manufacturing approach can leave sponsors restricted in their ability to respond to these kinds of changes, JTM supports sponsors to adapt, achieve earlier start-ups, improve reaction time to demand changes, and realize more sustainable supply chains.

To realize these benefits, reduce waste and optimize supplies, JTM must be approached correctly at the time of MAP development. Proactive planning to incorporate JTM can make the process faster, easier, and increase the likelihood of achieving optimal results.

Furthermore, a robust pre-production phase is needed to establish a quick pack, label, and quality release cycle for unlicenced medication. This means developing blueprints for receipt of unlicensed medication at packaging and labeling facilities, agreeing on pack design details, procuring kit components, and translating label text for initial participating countries.

Master packaging specifications will also need to be created within an enterprise resource planning (ERP) system to define each finished good by country, expiration date known at the time, and unique lot number. The ERP will also need to maintain the components required to make future kits, including the assigned bulk drug lot, the approved master label and label variables.

If appropriate planning takes place during pre-production, JTM production and distribution can be completed rapidly, with orders received, validated, and translated to a label work order and assembly work order via the ERP. Labels can then be printed, checked, and approved by quality control for use in the JTM pack and label operation.

MAPs represent an opportunity for sponsors to uphold ethical and regulatory responsibilities to patients with an unmet medical need. More than this, they have the potential to support sponsors to expand their own horizons by driving cost-efficiencies, capturing real-world data in support of commercialization goals, and building strong relationships with a range of key stakeholders. By harnessing JTM as a supply chain solution for MAPs, sponsors can look to maximize these opportunities and deliver production strategies that support speed, agility, and patient centricity.

Margaret Radford is unlicensed medicine services manager, and Lyn McNeill is Just in Time Manufacturing Solutions manager, both at Almac Clinical Services.

Challenges that can prevent sponsors realizing the full potential of managed access programs can be overcome by embracing a just-in-time manufacturing strategy.   

Understanding the Benefits of Harnessing Just in Time Manufacturing as a Supply Chain Solution for Managed Access Programs

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On Dec. 23, 2024, the World Health Organization (WHO) provided an update on COVID-19 vaccine antigen composition, pointing to the continued evolution of variants of the virus. A review of data has resulted in the recommendation that the current COVID-19 vaccine antigen composition, monovalent JN.1 lineage variant(NextStrain: 24A, GenBank: PP298019, GISAID: EPI_ISL_18872762), be used to enhance neutralizing antibody responses to JN.1 and its descendants. Vaccine antigens from more recent variants or alternative formulations is also a possible approach.

WHO’s Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC) has been monitoring genetic and antigenic evolution of SARS-CoV-2 variants and the performance of COVID-19 vaccines against these variants. WHO then advises manufactures of vaccines and regulatory authorities on implications of updates to the vaccines.

In December 2024, the TAG-CO-VAC met to review the evolution of SARS-CoV-2. Also discussed were the immune responses to the infection and vaccination. Currently approved COVID-19 vaccines were evaluated by the advisory group, which then provided an update on antigen composition. Previously, in April 2024, the group recommended the use of a monovalent JN.1 lineage vaccine antigen in response to JN.1 and its descendants. Manufacturers responded by updating their COVID-19 vaccine antigen composition to monovalent JN.1, with some of these approved by regulatory authorities.

The TAG-CO-VAC reviewed evidence that included the SARS-CoV-2 genetic evolution, antigenic characterization of previous and emerging SARS-CoV-2 variants, immunogenicity data on antibody responses seen in approved vaccine antigens, preliminary immunogenicity data on immune responses, vaccine effectiveness estimates of approved vaccines against XBB.1 and JN.1 lineages, and preliminary preclinical data and clinical immunogenicity data on candidate vaccines. The evidence, according to WHO, show that SARS-CoV-2 continues to circulate globally, resulting in severe disease and death, especially in people 65 years and older and/or with existing conditions, and current variants are all derived from JN.1. Based on data using antisera, it appears thatcirculating JN.1-derived variants (JN.1, JN.1.16.1, KP.2, KP.2.3, KP.3, KP.3.1.1, LB.1 and XEC) are antigenically closely related. Data from vaccination frommonovalent JN.1 or KP.2 antigens showed a significant increase in neutralizing antibody titers that cross-reacted with all JN.1 descendent lineages tested.

“The weekly proportion of XEC sequences among all SARS-CoV-2 sequences submitted to GISAID continues to increase, while the weekly proportions of all other Variants of Interest (JN.1) or Variants Under Monitoring (KP.2, KP.3, KP.3.1.1, JN.1.18 and LB.1) are now declining,” WHO stated in a press release (1). “There are other JN.1-derived variants that are currently in low proportions, but which have mutations that may give them an advantage over XEC: currently LP.8.1, NP.1, LF.7.2 are variants being monitored and/or characterized.”

There are limitations to the data that were available for review, however, according to WHO. Gaps have been seen in the reporting of cases, hospitalizations, and deaths from WHO Member States. It is also hard to predict the timing of mutations and emerging variants, the organization said in the statement. Immunogenicity data against current variants are also not available for all COVID-19 vaccines. In addition, there are limitations in the number and geographic diversity of studies.

“Although neutralizing antibody titers have been shown to be important correlates of protection from SARS-CoV-2 infection and of estimates of vaccine effectiveness, there are multiple components of immune protection elicited by infection and/or vaccination,” said WHO. “Data on the immune responses following JN.1 descendent lineage infection or monovalent JN.1, KP.2 or XBB.1.5 vaccination are largely restricted to neutralizing antibodies. Data and interpretation of other aspects of the immune response, including cellular immunity, are limited.”

The TAG-CO-VAC is encouraging the generation of more data and the further development of COVID-19 vaccines. “The TAG-CO-VAC will continue to closely monitor the genetic and antigenic evolution of SARS-CoV-2 variants, immune responses to SARS-CoV-2 infection and COVID-19 vaccination, and the performance of COVID-19 vaccines against circulating variants,” WHO stated in the release. “The TAG-CO-VAC will also continue to reconvene every six months to evaluate the implications for COVID-19 vaccine antigen composition.”

1. WHO. Statement on the Antigen Composition of COVID-19 Vaccines. Press Release. Dec. 23, 2024. 

https://www.who.int/news/item/23-12-2024-statement-on-the-antigen-composition-of-covid-19-vaccines 

Pointing to the continued circulation and evolution of COVID-19, WHO published a statement on the COVID-19 vaccine antigen composition to respond to variants of the virus.

WHO Provides a Statement on COVID-19 Vaccines

Roche has launched its cobas Mass Spec solution upon receiving the Conformite Europeenne (CE) mark approval for the product, including its cobas i 601 analyzer and what the company noted in a Dec. 18, 2024  press release is the first Ionify reagent pack of four assays for steroid hormones (1). The CE mark represents the first milestone in the global launch of the cobas Mass Spec solution. The offering aims to bring automated, integrated, and standardized clinical mass spectrometry testing to routine laboratories globally.

Following the launch, Roche will roll out a cobas Mass Spec solution menu offering that comprises more than 60 analytes for testing steroid hormones, vitamin D metabolites, immunosuppressant drugs (ISD), therapeutic drug monitoring (TDM), and drugs of abuse testing (DAT). The new offering will handle sample preparation through to result interpretation, and with it, Roche will be consolidating four technologies—ion selective electrode (ISE), clinical chemistry, immunochemistry, and mass spectrometry—onto a single platform, which the company expects will maximize efficiency and deliver enhanced medical value. The solution is designed to enable smart testing by leveraging physical and digital connectivity with other analytical units (2).

“The cobas Mass Spec solution will fundamentally change the field of clinical diagnostics,” said Matt Sause, CEO of Roche Diagnostics, in the press release (1). “The solution would make fully standardized clinical mass spectrometry more broadly available with the potential to improve patient care worldwide. For example, in breast cancer patients receiving hormone therapy, mass spectrometry can help physicians detect subtle changes in therapeutic response earlier, allowing for timely adjustments to treatment.”

Because mass spectrometry offers high specificity, sensitivity, and accurate analysis, it is considered the diagnostic “gold standard” for various clinical applications, such as measurements of steroid hormones in endocrinology, vitamin D testing, and the monitoring of immunosuppressants and therapeutic drugs, according to Roche in the press release. Mass spectrometry can benefit healthcare systems by, for example, monitoring the effective and responsible use of antibiotics as well as ongoing monitoring of disease progression and treatment. In addition, the high specificity of testing can provide greater levels of clarity to physicians, which would enable them to make more timely treatment decisions for patients.

In the meantime, Roche’s development of new, proprietary chemistry technology makes commercial automation possible and enables a workflow that is much more environmentally sustainable than current methods. “Until now, mass spectrometry has only been offered by specialist laboratories due to the low level of automation, integration and standardization, and the high complexity of the workflows that require highly skilled operators. This has resulted in great variability between different laboratories and long processing times,” the company stated in its release (1).

The cobas Mass Spec solution will be included in Roche’s established cobas pro integrated solutions product line, which enables full integration into clinical chemistry and immunochemistry testing as well as lab automation and IT.

1. Roche. Roche Transforms Mass Spectrometry Diagnostics with Launch of Cobas Mass Spec Solution. Press Release. Dec. 18, 2024.
2. Roche. cobas i 601 Analyzer. 

The launch of Roche's cobas mass spectrometry solution will bring fully automated mass spec analysis to the clinical lab. 

Roche Introduces New Mass Spectrometry Analyzer

The European Medicines Agency (EMA) announced on Dec. 18, 2024 that the agency, along with the Heads of Medicines Agencies (HMA) have revised their guidance on identification of commercially confidential information (CCI) and personal data used in marketing authorization applications as part of their commitment to transparency in the disclosure of information in response to access-to-document requests and the publication of data for authorized medicines.

The original 2012 guidance document offered, for the first time, a common approach for European regulators to use in order to identify parts of an application dossier that can or cannot be released publicly. EMA and national competent authorities have gained experience since then in the handling of access-to-documents requests and have applied more transparency when data is released. Therefore, EMA stated in a press release that it was necessary to review the 2012 guidance to align with current day-to-day practices and harmonize those practices across authorities. The revised guidance also applies to EMA’s 2014 proactive clinical data publication.

“As a general rule, the overwhelming majority of data in marketing-authorization applications is not considered CCI,” EMA stated in the press release (1). “The exceptions mainly relate to information about the manufacturing of a medicine, as well as information about facilities or equipment and some contractual arrangements between companies. While considered CCI at the time of the initial guidance, general information related to quality is now mostly considered releasable.”

The revised guidance considers information as “releasable by default” instead of applying a yes or no rule to an entire section of a dossier when determining which data can be released. Detailed practical orientations are provided for specific points that may be redacted or made anonymous within each section of the dossier. The guidance’s annex has also been updated to include examples of information that may be considered CCI or protected personal data.

How personal data are to be protected when it might lead to identification of a person is also detailed in the guidance. The revised guidance considers recent data protection legislation in the European Union, including the EU General Data Protection Regulation and Data Protection Regulation for the European Union. Identifying personal data of experts, staff, or patients that should be made anonymous is also addressed in the guidance.

The revised guidance went through public consultation in 2024 and report of the analysis from that consultation will be published in 2025.

The EU has been proactive over the past several years regarding data protection. In September 2024, EMA and HMA published recommendations for staff in the European Medicines Regulatory Networks about the use of generative artificial intelligence in large language models (LLMs), stating it could create potential data security risks (2). These guidelines are part of the HMA/EMA Multi-annual AI Workplan 2023–2028, published in December 2023, to be a guide for the use of AI in managing risk and maximizing benefits of AI.

1. EMA. A Common EU Approach to Data Transparency in Medicine Regulation. Press Release. Dec. 18, 2024.
2. Barton, C. Responding to the Increased Use of Generative AI. 

https://www.pharmtech.com/view/responding-to-the-increased-use-of-generative-ai

Revised guidelines published by EMA and HMA update the rules on identification of commercially confidential information and personal data used in marketing authorization applications.

Protection of Personal Data in European Medicine Regulation

Roche announced results on Dec. 19, 2024 from a Phase IIb study (PADOVA) where prasinezumab, an investigational monoclonal antibody (mAb), failed to achieve statistical significance, missing the study’s primary endpoint. The study involved 586 patients with early stage Parkinson’s disease (PD) who were treated for a minimum of 18 months while on stable symptomatic treatment. Prasinezumab demonstrated potential clinical efficacy in the primary endpoint, which was time to confirmed motor progression, with a hazard ratio (HR)=0.84 [0.69-1.01] and p=0.0657, missing statistical significance, according to a company press release (1). The effect of prasinezumab, as evaluated in a pre-specified analysis, was more pronounced in the patients (75% of the participants) who were treated with levodopa, with results showing a HR=0.79 [0.63-0.99]. It was also observed that consistent positive trends occurred across multiple secondary endpoints as well as exploratory endpoints.

Prasinezumab also remains well tolerated and no new safety signals were observed in the study. Roche is evaluating the data further and will work together with health authorities to determine what steps to take next.

“Parkinson’s is complex and devastating with no disease modifying treatment options available for the millions of people impacted,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, Roche, in the press release (1). “We believe the consistent efficacy trends from the Phase IIb study of prasinezumab merit further exploration. We will continue our close collaboration with the Parkinson’s community as we further evaluate the data to determine next steps.”

Both a Phase II study (PASADENA) and this Phase IIb study (PADOVA) will continue to give Roche a chance to explore the observed effects in both studies. Full results from the Phase IIb (PADOVA) study are expected to be presented at an upcoming medical meeting.

Prasinezumab is part of a licensing, development, and commercialization agreement that Roche entered into with Prothena, an Ireland-based late-stage clinical biotechnology company with expertise in protein dysregulation. Under the agreement, formed in December 2013 (1), the companies aim to develop and commercialize mAbs that target α-synuclein, a presynaptic neuronal protein that is genetically and neuropathologically linked to PD (2). Prasinezumab targets the build-up of α-syn protein in the brain, which can potentially prevent further accumulation and spreading between cells. This action can slow down the progression of the disease (1).

“The results from the Phase [IIb] PADOVA study are a significant step forward to potentially bring the first disease-modifying treatment option to the millions of individuals living with Parkinson’s disease and their families,” said Gene Kinney, PhD, president and chief executive officer, Prothena, in that company’s press release (3). “As pioneers in developing the first anti-alpha synuclein targeting antibody, we look forward to Roche presenting the results from the PADOVA study at an upcoming medical conference and sharing with health authorities to determine the most appropriate path forward.”

1. Roche. Roche’s Phase IIb Study of Prasinezumab Missed Primary Endpoint, but Suggests Possible Benefit in Early-Stage Parkinson’s Disease. Press Release. Dec. 19, 2024.
2. Stefanis, L. α-Synuclein in Parkinson's Disease. 

 (2), a009399. DOI: 10.1101/cshperspect.a009399.
3. Prothena. Roche’s Phase IIb Study of Prasinezumab Missed Primary Endpoint, but Suggests Possible Clinical Benefit in Early-Stage Parkinson’s Disease. Press Release. Dec. 19, 2024.

Results from a Phase IIb study missed the primary endpoint by failing to achieve statistical significance. 

Prasinezumab Misses Primary Endpoint in Roche’s Phase IIb Study, but Has Potential in Treating Early Stage Parkinson’s Disease

Nicolas Pivet Cytiva discusses automation benefits process development analytics

Process Development Benefits from Automated Analytical Technologies

In an interview with the PharmTech Group, Nicolas Pivet, vice-president and general manager, Technology Solutions at Cytiva, notes that among the challenges in developing a biomanufacturing process is the process analytical technology (PAT) used in that process. Pivet discusses how automation benefits process development, especially when applied to analytics.

“I would say digital documentation is always helping with fast regulatory filing and tech transfer,” Pivet says, adding that, “What we've been experiencing in Cytiva is that many of our customers actually use a platform approach for process development, which is great for speed, but sometimes is not optimized for everything.”

“The introduction of recipe-driven equipment in process development has really enabled 24/7 utilization of labs, so, it's really enhancing the throughput of your lab staff,” Pivet says. The scientist, therefore, with the help of automation, can program lab equipment to rapidly execute experiments and collect samples. “What we've been seeing as well is that SCADA—the supervisory control and data acquisition system—is a layer that allows equipment information to be viewed together. That's why, in Cytiva over the past seven years, we've been developing our Figurate automation offering, which is a wide range of automation solutions and libraries, from historian to control systems with Unicorn [a control software] to SCADA with Wonderware [an automation platform] and to DCS [distributed control system] with Delta V and PlantPAx [types of DCS].”

In the area of PAT, Pivet feels that the bio/pharma industry needs to move faster. In the sensors space, for example, P80 sensors have been seeing an emergence of improved sensing technology. “Measuring CQAs [critical quality attributes], for instance, inline or online is really the holy grail of the biopharma industry right now,” Pivet says. “…The industry needs to get there in being able to measure CQAs inline and helping with real-time release, or right-time release, of the drug product.”

Nicolas Pivet, Vice-President and General Manager, Technology Solutions, Cytiva

Nicolas Pivet is vice-president and general manager, Technology Solutions, at Cytiva, where his ability to find the right creative solution—whether for customers, or when writing songs—is at the root of his delivery-focused mindset. Innovation is second nature to Pivet, which allows him to bring fresh approaches to meeting customer needs. He is a seasoned leader, with laser-sharp customer focus and experience across software and hardware R&D, program management, strategy, service operations, and commercial. Since 2023, Pivet has led Cytiva’s global Automation, Digital and Learning Solutions Business Unit, developing digital solutions enabling fast, flexible, and reliable process development and manufacturing for the biopharma industry. He also leads the Manufacturing Capacity Solutions unit, where Cytiva supports customers with powerful and innovative end-to-end solutions that transform biomanufacturing.

Cytiva's Nicolas Pivet, vice-president and general manager, Technology Solutions, emphasizes how automation benefits process development, particularly in the analytical space.

In her end-of-the-year message, Emer Cooke, executive director of the European Medicines Agency (EMA) promoted the agency’s successes in 2024, including the recommendation of 114 drugs for approval, collaborations with EU Member States and regulators from other regions, and efforts to combat drug shortages.

Emer Cooke, executive director of EMA, is encouraged by the competitiveness of the European pharmaceutical market.

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