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Ed Trappler is president and founder of Lyophilization Technology, Inc. a contract research and technical services firm dedicated to freeze drying. He has over 40 years of experience in lyophilization that ranges from product development to equipment application engineering. He received his Bachelor of Science degree in chemistry at The College of New Jersey. His experience in the pharmaceutical industry includes product development, toxicology supply preparation, clinical manufacturing and parenteral production.
Denise L. Miller is document control specialist at Lyophilization Technology, Inc.
Carrie A. Shults is associate director at Lyophilization Technology, Inc.
Quality by design highlights product and process understanding and control, integrating quality risk management, and is also considered a quality system for managing a product’s lifecycle.
Target product profiles (TPPs), also referred to as quality target product profiles (QTPPs), are a summary of the proposed design attributes and characteristics of a finished drug product. TPPs are useful tools that assist in the fundamental principles of quality by design (QbD). TPPs are dynamic; they provide an initial introduction to the anticipated attributes inproduct design, to be further redefined as new knowledge is gained over the product lifecycle. As a method providing further focus on product attributes and to aid in the development process, potential critical quality attributes (CQAs) can be derived from the TPPs. As stated in the Guidance for Industry, Q8 (R2) Pharmaceutical Development, “CQAs are physical, chemical, biological, and microbiological properties or characteristics that should be within a certain specified range to ensure finished product quality” (1).
Throughout pharmaceutical development, the focus remains on establishing the CQAs. Initially identifying the desirable and essential CQAs, these and additional potential CQAs are modified and refined as knowledge increases through the development pathway. Many, if not all, of the developed CQAs become the basis of the final TPP. Essential CQAs become the final product release specifications (See Figure 1). The TPPs and CQAs result from enhanced product knowledge and, as such, aid in discussions with drug discovery, product development teams, clinical groups, manufacturing groups, as well as regulatory authorities. This knowledge allows for the further pursuit of improvements through QbD and risk-based decisions, along with product and process improvements. Per Q8, “Such a systematic approach can enhance the process to achieve quality and help regulators to better understand a company’s strategy.
Product and process understanding can be updated with the knowledge gained over the product lifecycle. A greater understanding of the product and its manufacturing process can create a basis for flexible regulatory approaches” (1).
QbD has been the industry focus because it offers the benefits of gaining greater product and process knowledge and understanding to all vested pharmaceutical development, manufacturing, quality, and regulatory groups. Knowledge-based decisions offer improved processes through systematic approaches and continuous improvement. Some of the benefits of a greater product and process understanding are greater product value, efficient and effective control programs, flexible regulatory approaches, fewer batch failures, and in the end, a greater return on investment and profitability.
Other benefits a company could realize are a decrease in post-approval submissions, proficient technology transfer to manufacturing, enhanced regulator confidence of robust processes, which result in reduced time to market, improved yields, lower cost, fewer investigations, increased drug availability, fewer recalls, and most importantly, consumer confidence (See Table I). QbD allows for first-time-right and lean assets management by using the risk perceptions. Thorough, proactive, and beneficial QbD begins with properly identifying TPPs.
From drug discovery, prior to and during development, TPPs are identified based on perceived attributes of the finished product. TPPs should be reexamined as new information and data become available. The basis for TPPs and resulting CQAs should be those that ensure a product is suitable for its intended use. For lyophilized parenteral products design, there are unique therapeutic regimens, inherent product requirements, and manufacturability of processing methods that are important to consider for product design criteria. Some of the aspects that need to be addressed are as follows.
Therapeutic regimen. Consider the frequency of administration. Is a multi-dose vial appropriate? The course of therapy should be addressed. Over what time period is this given? Does the product have adequate stability to support hold time in the constituted state?
The route of administration should also be considered. Will it be given intra-muscular (IM), subcutaneous (SubQ), intravenous (IV), peripherally inserted central catheter (PICC), or central line? What is required for the route of administration? What is the appropriate pH or isotonicity? What are the maximum volume allotments? For example, higher concentrations of citrate buffer can cause irritation at the injection site; tonicity and a high volume SubQ can cause pain or irritation at the site. Also consider if the therapy is or can be co-administered. Will there be compatibility with the equipment required such as needles or tubing?
Patient population and end user. Characteristics of the patient population should be determined. Is this a pediatric, adult, or geriatric patient? Are there excipient considerations for this population such as limiting L-Arginine use in pediatrics or sugar content for people with diabetes. For example, there are preferred excipients for lyophilized products.
Consider the disease state or health conditions of the patients. Are the patients immuno-compromised? Are there contraindications for excipients?
The type of end user should also be taken into consideration. Is the product to be used by the patient at home and/or be self-administered, if so, is the device capable of being self-injected? Is the end user a hospital, clinic, or IV therapy parlor? If administered in a pharmacy setting, is a multi-dose vial preferred? Will the product be used for emergency medicine, such as EMT, military, or remote environment? Will it require quick reconstitution and injection? Also, is end-user compliance required and are steps limited for ease of use?
Inherent product requirements. The following product requirements should be considered:
Stability under various conditions
Manufacturability of processing methods. The following processing methods should be considered:
CQAs are identified by quality risk management and experimentation to determine the effect of variation on product quality. Initial CQAs are refined as knowledge increases through the development pathway. Once identified, CQAs then need to be prioritized as essential or desirable through risk-based analysis to form a hierarchy of relative importance. Through pharmaceutical development and with a clinical-use perspective, the focus needs to remain on the essential CQAs. As the drug presentation progresses through pre-clinical development, laboratory and pre-clinical studies yield further insight into the achievable CQAs. These studies, as well as subsequent human clinical studies, aid in identifying CQAs as essential versus desirable, and the product knowledge base becomes greater. Drug product design warrants continued assessment and development of essential CQAs before the product moves from pre-clinical development and first-in-human clinical studies to Phase II clinical studies, and ultimately, commercialization.
Typical CQAs for solid dosage forms are aspects affecting purity, strength, stability, and bioavailability. For in-process controls and CQAs of lyophilized parenteral products, purity of the bulk solution when dealing with assay or absence of degradation could be defined by a product’s storage conditions or time. Another aspect of in-process bulk solution purity is microbiological and endotoxin, which limits are discussed within the United States Pharmacopeia(USP) <61>, Microbiological Examination of Nonsterile Products, USP <71> Sterility Testing, and USP <85> Bacterial Endotoxins Test (2, 3, 4). Strength needs to be considered as well as stability. CQAs specific to parenteral products include microbial aspects of sterility and endotoxin, physical properties of a parenteral product including both intrinsic and extrinsic particulates, chemical or biochemical aspects of assay and purity, as well as attributes of a lyophilized product of complete dissolution. Reconstitution time for complete dissolution of the dried product is also considered a CQA. The criticality of the reconstitution time may, however, be different and dictated by the clinical use aspects. For example, the reconstitution time for a product on an ER “crash cart” may be more critical than an antibiotic for prophylactic pre-surgery, reconstituted in a hospital pharmacy for administration the next day.
Stability entails conditions as a bulk solution, in the dried state during storage, as well as the constituted finished product. The ability to handle temperature excursions during storage is also important. In comparison, lyophilized products have different CQAs than ready-to-use parenterals. These additional finished product attributes are either direct or contributory. They include reconstitution time and volume and finished product testing in both the dried and constituted state. As an example, the product needs stability data and assay; these would be direct. However, they would be impacted by residual moisture, which would be contributory.
CQAs direct product in process and final product release specifications (See Table II). Specifically, for lyophilized parenteral products, reconstitution with a proper diluent and storage of the constituted solution can be extremely important if the product degrades quickly upon reconstitution. In any case, there needs to be an evaluation and an expiry for the product in a constituted state. As noted earlier, there may also be conditions that require a quick reconstitution such as a product on an emergency “crash cart.” As well, the product presentation, such as products in cartridges and syringes for a self-administered product, reconstitution time becomes paramount. Additional considerations should include excipient selection, excipient interactions, and container closure selection, to name a few.
Final commercial product profiles are instituted by the CQAs that direct targeted in-process assessments and final product release specifications. Assessing quality aspects for in-process measurements may utilize basic methods such as solution clarity, pH, and simple analytics such as UV/Vis for verifying concentration. Verifying the quality attributes of finish product entails a greater number of assessments using more sophisticated and both qualitative and quantitative methods. These can span simple tests such as pH, simple weights and measures such as content uniformity and deliverable volume, and dissolution, to higher level analytical methods such as sub-visible particles and stability indicating chemical and biochemical assays. In addition, sterile parenteral products, including those lyophilized, need to demonstrate they are free of microorganisms and have established endotoxin limits (5).
CQAs also need to be assessed and verified during the approved storage duration, up to and including the products expiry date. These specifications encompass all the same product attributes at the time of the batch release, including the absence of degradation products. It is also imperative to include not only the assay and purity upon initial reconstitution but also after the allowed storage interval for the constituted solution.
However, it is not only the physical product end-result that should be considered when reviewing TPPs and CQAs. Manufacturability considerations are paramount when a product progresses through design and development, to clinical, and ultimately commercial manufacturing. These considerations encompass processing time and compatibility of materials and the process capability within the intended manufacturing operation. Container closure selection also continues to be a focus, as batch size and yield in manufacturing, and space for distribution and storage at the final destination, are influenced by the packaging selected (6).
As product and process knowledge are gained and added into the dynamic TPP, the wealth of knowledge becomes a source of effective communication for technology transfer. The data can also be utilized in decision making, risk assessment, communications with FDA and sponsors, and in process validation. It lends to continual process improvements and control strategies as the product evolves to realization. It is an effective tool to streamline activities and manage risks starting with the end goal in mind.
In summary, establishing CQAs from TPPs for quality attributes of a parenteral product is an ongoing process that should originate during development and follow throughout the product lifecycle. This is an essential application of QbD principles and parallels those reflected in Q8 (R2) (1). This ever-evolving profile, when started early on in development with intended product attributes in focus, allows for increased understanding, communication, and quality. Among the benefits are a clear direction during development, improved processes, increased regulatory flexibility, and cost reduction. The result is a greater level of assurance that a product is suitable for its intended use and meets the needs and expectations of the end user.
1. FDA, Guidance for Industry: Q8 (R2) Pharmaceutical Development(Rockville, MD, November 2009).
2. USP, USP40-NF 35 General Chapter <61>, “Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests,” USP–NF 117-123.
3. USP, USP40-NF 35 General Chapter <71>, “Sterility Testing,” USP–NF136-143.
4. USP, USP 40-NF 35 General Chapter <85>, “Bacterial Endotoxins Test,” USP–NF163-169.
5. L. Daukas and E. H. Trappler, Pharmaceutical & Cosmetic Quality, 2, 5, 21-25 (1998).
6. M. J. Akers and J. Michael, “Sterile Product Packaging Systems” in Sterile Drug Products: Formulation, Packaging, Manufacturing, and Quality, J. Swarbrick, Ed. (Informa Healthcare Inc., New York, NY, 2010), pp. 29-47.
Vol. 42, No. 6
When referring to this article, please cite it as D. L. Miller, C. A. Shults, and E. H. Trappler, "Identifying TPPs and CQAs for a Lyophilized Parenteral Product," Pharmaceutical Technology 42 (6) 2018.
Denise L. Miller is document control specialist; Carrie A. Shults is associate director, Development Sciences; and Edward H. Trappler is president-all at Lyophilization Technology, Inc.