QUALITY DURING THE PRODUCT DEVELOPMENT PHASE

3. QUALITY DURING THE PRODUCT DEVELOPMENT PHASE

Many quality professionals in drug and device manufacturing define quality as conformance to specifications. Accordingly, appropriately set specifications are imperative to assure pro- duct quality. Researchers and quality professionals alike must assure that the product development process develops specifications that result in effectively monitored processes and process output. Numerous and repetitive objections from industry regulators have focused on inadequacies in specifica- tion quality. Regulatory actions have occurred because key quality attributes are not addressed in specifications or they have been inappropriately set. For the medical device indus- try the FDA has issued new regulations that give detailed requirements for specification development. Known as the Quality System Regulations, y these new regulations focus on the importance of pre-production quality and the specifica- tion setting process.

The traditional role of the QC department has been to assure conformance to specifications. If the specifications are set improperly, the QC department will likely not be able to detect a problem, prospectively. The QC department is

The characteristics that impart safety and efficacy to the product. y QSRs, previously known as the Device GMPs, Ref. 21CFR820.

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usually not involved in the development or setting of specifi- cations. Instead, the QC department’s role is to assure that there is a sound process for specification setting and that pro- duct specifications are complied with. Researchers developing and setting specifications should not, therefore, consider the QC department a safety net for bad design or its conse- quences. Signs of improperly set specifications are high man- ufacturing loss or scrap rates, excessive laboratory retest rates, stability failures, and customer complaints. Since the design requirements for products typically come from clinical or customer requirements and expectations, the collection of this information is essential in the specification development and setting process. The timing of when specifications should

be established and other key activities such as validation and regulatory filing is shown in Fig. 1 . The impact of measurement, raw materials, and proces- sing variation on clinical effectiveness must be addressed. Due to the sheer number of variables involved, statistical tools are commonly used to delineate variables that do or do not impact product performance. The results of these experi- ments dictate what specifications should be routinely mea-

sured. For example, Table 2 shows the results of varying product components with the resultant quality attribute. Other experimentation would be required to understand the relationship between product quality and processing vari- ables in the factory. These relationships should be established and well understood prior to setting final product and process specifications.

3.1. Metrology For departments generating process and product specifica-

tions, it is important not to overlook or underestimate the importance of manufacturing process capability and test method adequacy. Those individuals setting specifications must be aware of manufacturing capability (i.e., the assur- ance of reliably and consistently operating within developed specifications). Also, as process and product specifications are being established, there must be an assessment on

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Figure 1 Chronological milestones in injectable product development.

Table 2 Examples of Variation and Effect Variation in

Will have an impact on Types and concentrations of oils

Drug solubility and dose Types and concentrations of

Flocculation and coalescence phospholipids Types and concentrations

Flocculation and coalescence of auxiliary emulsifiers Types and concentrations

Solubility and crystal growth of solubilizers pH and buffering agents

Zeta potential, chemical stability Types and concentrations

Chemical stability of antioxidants Type and concentrations

Preservative effectiveness of preservatives

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metrology adequacy. Researchers and developers should ask: ‘‘Are the test methods that measure compliance to these materials and process specifications adequate to provide con- fidence levels required?’’ For example, is the inherent mea- surement error of the test method understood in relationship to the specification range for the quality attribute being measured? If the test method has a measurement error of

100 whether a measurement is or is not in conformance to the spe- cification. Similarly, if researchers set processing specifica- tions tighter than the factory can control or measure, trouble will soon follow.

3.2. Product Quality and Processing For injectable dispersed drugs, there are numerous routine

specifications to be assured prior to batch release or sale ( Table 3 ). Testing these product attributes confirms that the batch was properly formulated, processed, and packaged.

While there are many routine tests required for product batch release in manufacturing, additional tests are required to establish objective evidence that the product works and performs as intended. These tests may be addressed in either the research and development stage or in the marketed product stage, or both, for injectable dispersed products.

3.3. Process Analytical Technology Due to the advent of new measurement technologies, such as

near infrared, Raman, and other spectroscopic techniques and sensor technologies, the pharmaceutical industry and the FDA are moving toward increased in-process and final pro- duct control measurements of product quality. Process Analy- tical Technology (PAT) allows manufacturers the potential to quickly and non-destructively analyze each unit of finished product for certain product parameters such as particulate size, moisture content, oxygen content, content uniformity, and other critical quality features.

Quality and Regulatory Considerations 595 Table 3 Typical Marketed Product Batch Release Testing

Physical

Microbiological pH

Chemical

Active ingredient Sterility identification Particulate matter

Active ingredient Endotoxin

assay

Dispersion properties Key component (fat globule size =distribution

assay (include for emulsions and particle

wetting agents for size =distribution for suspensions)

suspensions) Packaging related specifications

Key component such as fill volume, labeling,

identification closure system, etc. Heavy metals Single related

substances Total related substances

3.4. Batch Testing Specifications call for routine QC testing of each batch of

finished product. These specifications are intended to demonstrate process control and product fitness for use.

pH: The pH test confirms proper processing. In-process pH measurements may also be required to assure proper ionic conditions for component processing.

Particulate matter: The USP defines acceptable limits for particulate matter in injectables. For products that are essen- tially particulate in nature, the particulate specifications are intended to control or eliminate unintended foreign particu- late matter from the product. Again, special test methods must be developed to distinguish between the product and unintended particulate matter.

Dispersion properties (particle size and size distribution): Size and distribution of drug particles define the dispersed product’s clinical effectiveness. Understanding the relation- ship between these attributes and medical effectiveness should be confirmed in clinical studies. Test methods for

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sizing can be technically challenging and should be designed to be robust and rugged for use in the QC testing laboratory.

Active ingredient identification: This ID test assures that the proper material was added during manufacturing. Active ingredient assay: This test assures the correct concentration of the active ingredient. Key component assay: This test, or series of tests, assures the correct concentrations of other batch ingredients such as excipients.

Sterility test: The product must be sterile when dis- pensed and must stay sterile upon repeated use, if packaged as a multi-dose formulation. Terminal sterilization using heat is not always possible and aseptic manufacturing must be stringently controlled. Validation of the sterility test method is required. Emulsions and suspensions can provide special challenges due to the techniques used, such as filtration and direct inoculation. See Special Considerations.

Endotoxin test: Injectables must meet USP requirements for pyrogens or bacterial endotoxin. Dispersed products provide special challenges in pyrogen control since these pro- ducts cannot be depyrogenated using typical methods. Instead, manufacturers of these products must focus on the prevention of pyrogen introduction into the formulation or from development of pyrogens during manufacturing. Testing for pyrogens is also problematic with these formulations. Due to the physical nature of many suspensions and emulsions, the USP Pyrogen Test (using rabbits) is not always possible. Instead the USP Bacterial Endotoxin Test has to be the logical alternative. Whatever test is selected the absence of potential interference of test sensitivity by the dispersed phase of the product should be addressed in the pyrogen or endotoxin test method validation.

Fill weight =volume: These tests confirm gravimetrically that the individual containers contain the stated mass of material.

* Typical methods include rinsing, dilution, distillation, ultrafiltration, reverse osmosis, activated carbon, affinity chromatography, or dry heat.

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Package integrity: A representative number of units from the batch are checked to assure proper closure system integ- rity. This can include destructive testing such as pressure tests (charge container with pressure and look for bubbles underwater) or non-destructive testing such as visual checks, sonic, electrical, or other tests designed to confirm the drug container =closure system has no leaks and will withstand normal handling without breaches in integrity.

3.5. Required Additional Testing Several other tests are important to the quality of injectable

dispersed products. While these tests are not performed on each batch of injectable product, they are conducted during pre-market activities such as clinical material manufacturing and validation studies:

Physical stability testing: The effects of time, storage conditions, packaging, and transportation must be established. Stability programs are designed to gain this understanding. Stability programs should assure a product meets its label claim throughout the stated shelf life (expiration date). There typi- cally are two stages in stability testing; R&D stability and mar- keted product stability. In the R&D stages material may be stressed to predict real life performance over intended dating. At this stage special storage and handling considerations are confirmed. Once a product is approved and in production a select number of batches per year are placed on stability to monitor product performance in its current configuration. These marketed product stability lots are typically monitored at the storage requirements stated on the label. Each product on the marketed product stability program should have a protocol that dictates storage conditions, test intervals, sampling, and test requirements.

Syringeability and injectability testing: The ease of with- drawal of a product from the container (syringeability) and its subsequent ejection into the desirable site of administration (injectability) must be determined for the final formulation. Syringeability can be affected by the diameter, length, shape of the opening, and surface finish of the syringe needed and,

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therefore, should be characterized in specification and pro- duct labeling development. Injectability denotes the ease with which a dose can be injected. The injection medium must be understood and also characterized during product development.

Preservative effectiveness testing: Multiple-dose inject- ables contain preservatives to safeguard the product against in-use microbial contamination. The USP preservative effec- tiveness test method is typically used. The water-insoluble dispersed phase may present special problems in development of a good preservative system. These same product related issues impact the development and qualification of sterility test methods as well. The problems occur because the parti- cles of the product interfere with microbial test methods that rely on turbidity as indicators of microbial growth.

4. RAW MATERIALS Consistent product performance and manufacturing require

quality ingredients. Many key ingredients of dispersed pro- ducts are biologically provided, meaning variation will be higher than chemically synthesized materials. The natural variation of biologically derived raw materials can cause pro- blems. The quality of complex fats and lipids can vary as well as the composition of ingredients such as soy and safflower oils ( Table 4 ).

Raw materials have stability profiles as do final pro- duct formulations. What is the effect of the supplier’s man- ufacturing date, the drug firm’s purchase date, and ultimate product performance? The drug development plan should include stability analyses of key component raw materials. Typically, retest or expiration dates are set for raw materials. Retest dates require the raw material be retested against the material specification. Acceptable results allow for material approval status to be extended to the next ret- est date. Expiration dates are just that (e.g., material has expired). Retesting expired material is not considered an accep- table GMP practice.

Quality and Regulatory Considerations 599 Table 4 Some Specific Raw Material Quality Control Issues for

Formulation Components of Dispersed Systems Trace quantities of gossypol in oils like cottonseed

Limits on hydrogenated oils, other saturated fatty materials Limits on unsaponifiable materials such as waxes, steroidal

components Contamination with herbicides and pesticides Vasopressor contaminants in soybean phosphatides Specifications on lecithin minor components such as cholesterol,

sphingomyclin, phosphatidic acid, and derivatives

4.1. Variation in Raw Materials Some suspension and emulsion stability problems have been

traced to seasonal variation in raw materials. Small shifts in complex, multi-constituent raw material components such as oils have caused unexpected changes in marketed product stability. A good technical relationship with key material sup- pliers is important to set sound material specifications and to troubleshoot when necessary.

Many fats and oils used in the manufacture of dispersed products come from natural sources. Accordingly, raw mate- rial quality is influenced by mother nature. In one example, shifts in oil fraction components (fatty acids) were detected in high grade soybean oil. The fraction ratio did not meet expectations. Investigation indicated that unseasonably cool and damp conditions in the Western Hemisphere shifted the soy plants production profile of fatty acids. Immediate corrective action was not possible. The manufacturer had to contact the appropriate regulatory body to decide on an accep- table course of action. The regulatory body had to make a quick decision to accept an amendment to the firm’s NDA. Working together the FDA and the pharmaceutical firm were able to assure that product quality and clinical efficacy would not be impacted by the shift in the soy oil fatty acid profile.

4.1.1. Raw Material Specifications Specification quality is key at all stages of manufacturing.

Raw material specifications are no exception. The process

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for establishing specifications is essential to assuring product performance, good supplier relations, and cost.

Raw material specifications should address the following elements:

List of approved suppliers, by location of manufacturer. Key elements of the formula. Chemical name and molecular weight. Sampling requirements including:

special handling considerations (safety, humidity, etc.); sampling plan (quantities, number of samples per container); approved sampling containers =materials; file or reserve sample requirements.

Specifications for acceptance of material for further processing including but not limited to:

receipt quality (any damage during shipment); proper container type and label on receipt; identity; solubility; purity, such as related substances, impurities, degradation products; quality, such as particle size, crystallinity, polymorphic form, etc.; microbial and =or pyrogen quality.

Testing procedures: compendial;

non-compendial, or as required by NDA.

4.1.2. Specific Raw Material Concerns Research and field experience have provided some insight

on potential problems with components of dispersed sys- tems. Impurities and traces of gossypol, an antispermato- genic pigment extracted from cottonseed oil, must be controlled.

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Hydrogenated oils and other saturated fatty materials vary seasonally and geographically. Unsaponifiable materi- als, such as waxes, are also highly variable and should be monitored closely. Volatile organic residues, herbicides, and pesticides are toxic at extremely low levels and difficult to detect. Refined chromatographic and spectrographic proce- dures are required to achieve low detection levels.

Minor components in lecithin such as cholesterol, sphin- gomyclin, and phosphatides also must be controlled to below detectable limits.

Microbial, endotoxin, and non-viable particulates are quality attributes that require specifications for injectable products. Assigning specifications for these factors at the raw material stage is important to assure proper QC through- out the manufacturing life cycle.

4.1.3. Toxicological Concerns Dispersed injectable products provide unique dosage forms

for life-saving therapeutic and diagnostic purposes. There are, however, some toxicological considerations. Emulsifiers have been shown to produce hemolytic effects. Lecithin may carry toxic impurities and nearly all emulsifiers possess potential toxic properties. Shifts in free fatty acid content can impact toxicity, stability and clinical effectiveness. Poor control of oil droplet size and size distribution can have unto- ward clinical implications plus there are clinical hazards asso- ciated with injecting these dispersed agents. Hazards include phlebitis, precipitation in the veins, extravasation, emboli, pain and irritation, and interactions with blood cells and plasma proteins.

4.2. Packaging Materials Selection and qualification of packaging materials are essen-

tial to long-lasting quality products. Due to the hydrophobic, non-polar nature of these formulations, there are fewer options for stopper compounds, tubing, and gaskets for man- ufacturing purposes, and primary containers such as vials,

IV bags, or syringes. Packaging Research and Development

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departments should develop or identify test protocols that will assure that packaging materials are inert and non-reactive for the required period of product contact. Product contact packaging materials such as vials, stoppers, syringe plungers and barrels, and administration tubing must be pyrogen-free when manufactured or rendered pyrogen -free via depyrogena- tion. In the final product configuration, the ‘‘integrity’’ of the drug delivery system must remain intact from manufacturing assembly to the time of use. Studies should be conducted to assure package integrity remains throughout the product’s intended life. Torture tests and challenging the closure system with microbes and =or endotoxin are common when validating the integrity of the container and closure system.

5. SCALE UP AND UNIT PROCESSING Laboratory batches do not normally translate directly to

industrial scale. Well-characterized raw materials, identifica- tion of critical process parameters, properly set process and product specifications, and suitable test methods are prerequi- sites for successful quality scale up operations. When scaling dispersed products, it is important to know where the sources of variability are and to reduce them wherever practical. High degrees of variation in materials, processes, or test methods can mislead researchers, especially when only a limited num- ber of batches or samples can be tested. Bioequivalence and stability should also be considered when significant batch size changes are made. Other in-process manufacturing controls that should be addressed are shown in Table 5 .