September / October 2019

Patient-Centric Specification: Regulatory & Pharma Industry Progress

Daniel Peng, PhD
Joel Bercu, PhD
Ann K. Subashi
Lawrence X. Yu, PhD
ISPE PQLI® Patient Centric Specification Working Group
Patient-Centric Specification: Regulatory and Industry Progress

On 5 June 2018, a plenary session entitled ”Patient-Centric Specification” (PCS) was held at the 2018 ISPE Quality Manufacturing Conference in Arlington, Virginia. More than 160 professionals from worldwide innovator and generic pharmaceutical companies, academia, and regulatory agencies attended. The objective of the session was to discuss the recent regulatory and industry progress on this topic. Attendees discussed the opportunities, challenges, and future directions for establishing patient-centric specification.


As defined in International Conference on Harmonization (ICH) Q6A,

Specification is a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use.1

The fundamental intent of this definition is to ensure that a drug product will deliver the therapeutic benefit to the patient as stated in its labeling (the intended performance).

However, interpretations of this ICH guidance by different regulatory agencies have diverged during the last two decades. Historically, it has been usual and customary to set drug substance (DS) or drug product (DP) specifications based on the variability observed in a limited number of clinical batches without consideration of the actual impact of the variability on patient safety and product efficacy. This practice has the potential to cause significant and deleterious consequences when applied to product specifications.

These consequences may include:

  • The unnecessary rejection of batches that would have met patients’ needs (safe and effective medicine), which could, in turn, lead to drug shortages
  • Unintentionally allowing manufacturers with poor manufacturing processes to broaden limits in their specifications
  • Limiting manufacturing process to 2 to 3 sigma, thereby reducing the flexibility of manufacturing changes and increasing manufacturing costs

To address these issues, ISPE established a patient-centric specification technical team under the Pharmaceutical Quality Lifecycle Implementation (PQLI)® Committee in Decem-ber 2016. Members of the team are volunteers from global pharmaceutical and biotech companies with expertise in toxicology; chemistry, manufacturing, and control (CMC) regulatory affairs; quality assurance; quality control; and Drug substance/Drug product development and manufacturing.

Since its founding, the team has had monthly meetings to discuss the opportunities and benefits of patient-centric specification and share their experiences in developing patient-centric specification in the global regulatory landscape. The objective of the session at the ISPE Quality Manufacturing Conference was to share the current views of the patient-centric specification team on this topic, especially as it relates to Drug substance/Drug product impurity specification limit setting. In addition, Lawrence X. Yu, Deputy Director of the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) was invited to give the FDA’s perspective on patient-focused quality standards. The following is a summary of the presentations and highlights from the panel discussion between the audience and the speakers.

Patient-Centric Specification and Impurity Qualification

Joel Bercu, Senior Director, Nonclinical Safety and Pathobiology, Gilead Sciences Inc., gave a presentation regarding the ISPE patient-centric specification team’s views on patient-centric specifications for Drug substance/Drug product impurity and impurity qualification using nonclinical approaches. He started the presentation by referring to the part of the ICH Q6A definition of specification stating that specifications “should focus on those characteristics found to be useful in ensuring the safety and efficacy of the drug substance and drug product.” He went on to explain the relationship between patient-centric specifications and batch data. Ideally, patient-centric specifications would be set inside the range of the acceptable safety/efficacy boundaries. These limits should be based on knowledge of the product and its intended performance (safety and efficacy) in patients. However, this fundamental focus on safety and efficacy is unfortunately sometimes obscured by the notion that batch manufacturing history is paramount to the setting of specification criteria at the point of registration.

After this general introduction, Bercu focused on the setting of acceptance criteria for drug substance impurity and drug product degradation products. He gave a high-level review regarding the source of impurities (Drug substance process impurity and Drug substance/Drug product degradation products), as well as the current ICH guidelines (i.e., ICH Q3A[R2], Q3B[R2], Q3C[R7], Q3D[R1], M7[R1], and S9) for the safety testing of impurities, residual solvents, heavy metals, and mutagenic impurities.2 ,3 ,4 ,5 ,6 ,7  He pointed out the qualification threshold is phase dependent. Values are recommended by ICH Q3A(R2)/Q3B(R2) for chronic exposure, and a qualification threshold is recommended for early-phase clinical trials less than six months in duration for nonmutagenic impurities.8  If the qualification threshold is exceeded, safety data are needed to justify the higher level of impurity. If an impurity is considered mutagenic, then a limit lower than the ICH Q3A(R2)/Q3B(R2) qualification threshold can be established using the threshold of toxicological concern (TTC) concept. If there is a sufficient amount of toxicology data for an impurity, a permitted daily exposure (PDE) or an acceptable intake can be developed based on the toxicity data.

However, Bercu explained, current practices for setting acceptance criteria rely heavily on process experience from a limited number of clinical batches using some statistical analysis (e.g., process capability, tolerance interval, or range from the minimum and maximum limits attained during development), rather than safety and toxicity qualification data. The “process experience-based” approach does not answer the question of whether the predicted variability will impact product safety and efficacy. In addition, it is unreliable without lengthy process experience. A minimum of 30 batches in a statistical control state may be necessary to provide a reliable forecast of variability of future manufacturing batches.9  Last, lowering the impurity specification is not always the best solution, as it can impact other quality attributes, resulting in more environmental waste and increased manufacturing costs. Therefore, he recommended leveraging the safety data to ensure appropriate patient-centric specifications and cautioned against being overly restrictive with impurity specifications based on limited batch data.

Ideally, patient-centric specifications (PCS) would be set inside the range of the acceptable safety/efficacy boundaries.

Case Studies and Global Regulatory Challenges

Ann K. Subashi, Senior Director, Global Regulatory Affairs CMC, Pfizer, Groton, Connecticut, shared three industry case studies on how to establish patient-centric specifications for Drug substance/Drug product impurities and discussed some of the global challenges arising from divergences in ICH guideline interpretation and implementation in different regions.

The first case study represented the global registration experience for one inorganic impurity attribute, palladium (Pd), in a chemically synthesized drug substance (small molecule). A limit of not more than (NMT) 500 parts per million (ppm) for Pd in the drug substance was initially proposed and was supported by the EMA 2008 Guideline10 and ICH Q3D5 , which allows for an 800-ppm limit based on the permitted daily exposure for Pd. The initially proposed specification limit (NMT 500 ppm) was accepted by ICH Regions 2 and 3. However, ICH Region 1 requested a tighter specification (NMT 200 ppm). The Region 1 request was related to two concerns: First, Pd offers no therapeutic benefit to the patient; second, in some cases, higher doses may be used for other indications, or additive exposure may occur due to combination use with other drug products. Notably, at the time of the registration, there was no discussion or plan that higher doses would be marketed; therefore, the dose concern from the country seemed to be unfounded. Addressing the second concern related to co-dosing and the potential for an additive exposure to Pd was a challenge because it was difficult for the applicant to determine the levels of Pd in other drug products that were not within its own portfolio. Furthermore, the defined permitted daily exposures already take into account the potential for exposure from multiple sources, so a safety factor is built into the permitted daily exposures. In this case, the company was forced to control the impurity to the lowest levels possible. A palladium scavenger step was developed, validated, and introduced postapproval to meet the Region 1 specification limit. The additional measure of control cost the research-and-development organization many months of development time, increased the overall cost of the commercial process, and added time to produce each batch of the active pharmaceutical ingredient.

The second case study was for an impurity that is also a significant metabolite in the drug product specification. The manufacturer initially proposed an NMT 0.8% limit for this metabolite based on product clinical absorption, distribution, metabolism, and excretion (ADME) and nonclinical toxicology data. This limit was accepted by ICH Regions 1 and 2. However, ICH Region 3 requested a tighter specification limit based on actual batch data. The applicant in turn used a safety-based argument showing that the in vivo level of this impurity was higher than the level in the proposed specification. However, the regulatory health authority insisted that the specification should be based on batch data and the mean plus 3 standard deviations, rather than accepting the justification based on holistic knowledge of the product and toxicology qualification data. After numerous rounds of communications, the applicant and the health authority compromised, establishing a final specification limit (NMT 0.4%) that fell between the originally proposed specification and the batch data results.

The third case study concerned unconjugated payload in an antibody drug conjugate (ADC) product comprising a monoclonal antibody (IgG4) conjugated via lysine chemistry to a calicheamicin derivative. Nonclinical toxicology data evaluating the conjugate and unconjugated payload provided evidence that the toxicity profile of the antibody drug conjugate principally related to nonspecific binding of the conjugate rather than from the unconjugated payload. A limit (NMT 4.0%) for the unconjugated payload in drug product was initially proposed and equated to a safety margin greater than an order of magnitude (1/25) from the no observed adverse effect level (NOAEL) for the unconjugated payload. Region 4 approved the acceptance criteria based on the safety margin. However, Region 2 approved a limit of NMT 2.0% based on the maximum value observed in the clinical batches, and Regions 1, 3, 5, and 6 approved a specification limit of NMT 3.1% based on a tolerance interval calculation using data from the eight clinical batches.

These three case studies clearly illustrate divergence among the different health authorities regarding the appropriate basis for establishing the acceptance criteria for Drug substance/Drug product impurities. There is no evidence that the differences in quality standards actually bring any value to patients or improve product safety. However, it is certain that varied quality standards for a product increase the complexity in pharmaceutical quality systems as well as supply and distribution plans. This increased complexity in turn leads to increased costs and the potential for issues with supply continuity.

Patient-Focused Quality Standard

Yu gave a presentation on the FDA’s perspective regarding patient-focused quality standards. He stated that a product is of high quality if it is capable of reproducibly delivering the therapeutic benefit to the consumer as stated in the label, is free of defects, and presents no undeclared risks. A patient-focused quality standard is a criterion to which a drug product should conform to deliver the intended therapeutic benefit. Establishing such standards can help not only reject batches with poor quality but also increase flexibility in pharmaceutical manufacturing by preventing too high a reliance on process capability to establish quality standards. Patient-focused quality standards support the FDA’s vision of “a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drugs without extensive regulatory oversight”.11

Quality standards under the quality-by-testing paradigm are established based on data from one or more batches. When testing must be done to re-lease batches, acceptance criteria could be overly sensitive, unnecessarily rejecting batches that would have met patients’ needs, or acceptance criteria could be insufficiently sensitive, rewarding manufacturers with poor manufacturing processes and controls. In contrast, under the quality-by-design paradigm, acceptance criteria are established based on patient impact. Yu noted that testing may not necessarily be needed to release batches,12  and acceptance criteria should be decoupled from process variability/capability.

Recently, the FDA issued a manual of policies and procedures (MAPP 5017.2) on establishing impurity acceptance criteria13 and a dissolution guidance for immediate-release, solid-oral-dosage-form drug products containing highly soluble drug substances.14  The impurity MAPP provides information about establishing impurity acceptance criteria. It documents the CDER practice of focusing on the needs of patients rather than the manufacturing process in evaluating impurity specifications. The dissolution guidance establishes standard dissolution methodology and acceptance criteria that are appropriate for highly soluble drug substances that are formulated in immediate-release dosage forms. The guidance recommends that the drug product dissolution acceptance criterion be based on the high solubility of the drug substance, with a recommended single-point dissolution specification of 80% in 30 minutes—rather than an unnecessary multiple-points dissolution specification—for an immediate-release solid oral dosage form containing a high-solubility drug substance as defined per the Biopharmaceutics Classification System (BCS). Both the FDA impurity MAPP and dissolution guidance move the FDA to the direction of patient-focused quality standards.

Yu also pointed out that, moving forward, the FDA will encourage the development of patient-focused dissolution standards for extended-release dosage forms. It is hoped that future in vitro dissolution testing for an extended-release dosage form would be more predictive of the dosage forms in vivo performance. The impact of critical material attributes and critical process parameters on in vivo performance could then be quantitatively assessed by in vitro dissolution. This will provide scientific and risk-based knowledge to support patient-focused quality standards to ensure high-quality drug products that maintain safety and efficacy throughout the product life cycle.

Panel Discussion

Question 1 (asked by Yu): Can industry collect more case studies to show the global regulatory divergence that industry is facing?

Daniel Y. Peng, Director in Global Regulatory Affairs CMC Biologics at Merck, responded: Yes, the ISPE patient-centric specification team is working with member companies to collect more case studies to holistically understand the magnitude of the global divergence of specifications setting.

Subashi elaborated regarding the challenges that pharmaceutical companies are facing regarding global submissions and commercial specification negotiations during application review. The negotiations for specification setting often happen independently for each market or region and typically occur while seeking initial market approval, when the pressure is on to get the product to market. At the end of the day, particularly for complex products, the applicant ends up with manufacturing based on the most restrictive criteria to ensure global supply. This means that just one market with a different view can severely impact manufacturing operations and significantly increase complexity in pharmaceutical quality systems and supply and distribution plans. This complexity could ultimately lead to increased costs and potential issues with supply continuity. It would be very helpful if industry and global regulators could talk more openly about the science behind the rationale as well as what the real risks are. Efforts toward more harmonization based on patient-centric specification criteria could bring significant value.

Question 2: (to Yu) Can you share with us the implementation status of the MAPP (5017.2)? Has there been anything that’s happened with the reviewers in the Office of New Drug Products (ONDP) and the Office of Lifecycle Drug Products (OLDP), and have you seen any differences regarding what’s being submitted in the application in terms of specification?

Yu responded: MAPP 5017.2 was developed by OPQ with representatives from all relevant OPQ suboffices, including ONDP, OLDP, Office of Biotechnology Products (OBP), and Office of Process and Facilities (OPF). It provides guiding principles and approaches for establishing drug substance and drug product impurity acceptance criteria for nonmutagenic impurities in new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs), based on the consideration of clinical relevance (safety and efficacy). The initial effective date of this MAPP was 18 January 2018. Hence, this MAPP has been already implemented in and followed by the OPQ suboffices focused on application assessment. Of course, if there is any significant issue or inconsistent assessment practice uncovered by industry, the FDA welcomes the applicant to have open communication with the agency.

Yu also clearly emphasized that even though the FDA wants to decouple the setting of acceptance criteria from process capability, manufacturing process consistency should be monitored and maintained during the production of the drug substance and drug product as part of the quality system.

He indicated that he has not seen any differences in terms of specification setting for different types of applications (Abbreviated new drug applications vs. New drug applications). He asked Stephen Miller, Branch Chief, Division of New Drug Product I, ONDP/OPQ/CDER/FDA, to further comment on this question regarding the assessors’ experience. Miller indicated that he was encouraged by the concept of MAPP 5017.2, which is in alignment with ICH Q3A/Q3B guidelines for impurities when there are established toxicology data, such as solvents or metals. When there are no toxicity data generated to support an impurity, the qualification thresholds as defined by ICH Q3A(R2) and Q3B(R2) are the standard and should be followed, and this consideration is included in the MAPP. This is also true for ICH M7, where the acceptable level of a mutagenic impurity is the threshold of toxicological concern. Miller questioned whether there are any cell-based or computational assays that can be used to determine the toxicity of a degradation product vs. traditional animal studies.

Bercu responded that there is not a good cell-based or computational assay that can represent the multiorgan toxicity as observed and obtained in an in vivo study. There is conservatism built into the traditional animal study. The NOAEL derived for an impurity in a qualification study is not a true NOAEL but a fraction of the NOAEL for the drug substance. Therefore, how we calculate toxicology-based limits for degradation products is inherently conservative.

Miller commented that he did not mean to single out degradation products except to note that they may be difficult to assess given that they are close to the toxicology-based limit from an animal study. Bercu responded that it is important to spike degradation products in a toxicology qualification study to help demonstrate a higher margin for the toxicology limit and the specification.

Question 3: Once a company has generated the animal toxicity data, how do you translate/back-calculate the limits for human beings?

Bercu responded: The approach as specified by ICH Q3A is to make sure the absolute amount or dose in animals is not exceeded in humans. However, some health authorities have requested lowering the acceptable dose by an additional factor, which is not recommended by ICH Q3A.

Question 4: What can industry and the FDA do to gain more acceptance for patient-centric quality standards globally?

Subashi responded: FDA MAPP 5017.2 is setting a clear direction and guiding principles for FDA OPQ assessors in assessing drug substance and drug product impurity limits in new drug applications, abbreviated new drug applications, and biologics license applications. Industry is pleased to see that the FDA is moving in this direction to accept acceptance criteria based on clinical relevance (safety and efficacy). The pharmaceutical industry needs to develop and share more case studies throughout the scientific domain to bring awareness to a wider audience, continue discussions between industry and multiple regulatory authorities in forums such as this plenary session, and pursue available efforts through joint reviews.

While the MAPP is helpful, influencing other guidelines is a priority for the future. While we may continue to see global divergence, we should be moving toward global convergence. Convergence of major ICH markets could go a long way in influencing the acceptance of patient-centric specifications globally.

Question 5: If the push is to manufacture to the most stringent criteria to achieve global supply but manage by exception, how are the exceptions documented in quality systems and inspection?

Subashi responded: We tend to avoid such situations. The palladium example is an excellent case for which we adjusted manufacturing process to meet the criteria. That said, it [the need for exceptions] can come up and ends up as a challenge in the quality and distribution systems to enable release to certain markets.

Question 6: Have you ever run into a situation where the manufacturing risk was so high when considering the regulator’s suggested specification criteria that you needed to push back hard and it could have impacted product approval?

Subashi responded: Yes, we have.

She then used as an example the third case study (the unconjugated payload), where Region 2 consistently pushed the applicant to tighten acceptance criteria that reflected the minimum/maximum of clinical exposure for multiple attributes even after the applicant had presented their view on what was relevant to patients. Considering the relatively limited numbers of batches used in clinical studies for that program and applying the tighter acceptance criteria to multiple attributes could lead to an extremely high batch-failure rate, which would result in the product not being commercially viable.

In this case, the applicant evaluated the practical implications and process capability for each attribute. They ultimately decided they could live with the tighter acceptance criteria. This is because the applicant improved the defined commercial process and updated the analytical methods where they did not have a high risk for failure anymore, even if they accept the tighter criteria as the health authority requested. Irrespective of having a patient-centric argument reflecting the toxicology understanding around why higher levels of unconjugated payload would not present a safety risk, the applicant decided it wasn’t worth continuing the debate when they had more significant issues to manage to gain approval and have a commercially viable product.


Highlights from the session are as follows:

  • A paradigm shift is needed for both industry and health authorities. Establishing patient-centric specification can help not only reject batches with poor quality but also increase flexibility in pharmaceutical manufacturing by decoupling the setting of specification acceptance criteria based on drug product safety and efficacy (voice of patient) from process capability (voice of process).
  • The ISPE team recommends leveraging the safety data to ensure the establishment of appropriate patient-centric specifications for Drug substance/Drug product impurities. One should be cautious about being overly restrictive regarding impurity specifications based on limited batch data.
  • There are limited examples of a patient-centric specification being successfully set. However, many efforts may be slowed by the significant divergences among the different health authorities regarding the basis for establishing appropriate acceptance criteria for Drug substance/Drug product impurities. Varied quality standards for a product in-crease complexity in pharmaceutical quality systems, as well as supply and distribution plans. This complexity in turn can lead to increased costs and potential issues with supply continuity.
  • The FDA Impurity MAPP (5017.2) and the recently published dissolution guidance clearly indicate that the FDA is moving in the direction of patient-focused quality standards.
  • Continued discussions between industry and multiple regulatory authorities are needed. Patient-centric specification could be an important cornerstone to achieve global harmonization.


The authors would like to thank the other members of the ISPE Patient-Centric Specification (PCS) Impurity Team: Susan Berlam, John Berridge, Barry Cherney, Darrin Cowley, Helen Laughton, David McLoughlin, Megan McMahon, Christine Moore, Cheenu Murti, Julia O’Neill, Rodney Parsons, Roger Quan, Andrew Teasdale, Stephen Tyler, and Timothy Watson. Thank you as well to the FDA officers and the audience for their contributions to the session.