Until recently, companies manufacturing Combination Device or Drug products were faced with the formidable task of deciding how to best comply with multiple, and sometimes overlapping, regulations for both devices and pharmaceutical products. When the FDA issued the final rule for 21 CFR Part 4, cGMP Regulation of Combination Products, on Jan. 22, 2013 and the Final Guidance for Industry on how to comply with these new requirements in Jan. 2017, much of the gray and conflicting areas were resolved and it became apparent that a either a Device based Quality System or a Pharma based Quality System, enhanced with policies and procedures to cover either the Pharma regulations or the Medical Device regulations, is the preferred route.

ProMed’s Combination Products QMS was derived from the existing ISO 13485 certified and 21 CFR 820 compliant device Quality System used in our molded products area. The key provisions of the Pharma regulations in 21 CFR 210 and 211 that are needed for us to manufacture devices with a drug constituent are identified in Table 1.

Table 1
Section Description
Section 211.84 Testing and approval or rejection of components, drug product containers, and closures.
Section 211.103 Calculation of Yield
Section 211.132 Tamper-evident packaging
Section 211.137 Expiration Dating
Section 211.165 Testing and Release for Distribution
Section 211.166 Stability Testing
Section 211.167 Special Testing Requirements
Section 211.170 Reserve Samples

This whitepaper examines ProMed’s approach to implementing QMS elements that satisfy these requirements.

Drug Product Containers & Closures (21 CFR 211.84)

This regulation defines the requirements for the testing and approval (or rejection) of components, drug product containers, and closures.

ProMed’s device Quality System uses risk evaluations to categorize our suppliers. Those vendors deemed critical are evaluated through assessments, audits, or both depending upon the level of risk. Components from critical vendors are qualified as required to assure we use only those components that meet customer specifications.

To comply with the additional pharmaceutical requirements, we enhanced our Pharma QMS to ensure that Drug components and Drug product containers are received using approved in-house procedures and, where cleanliness is a requirement, we assure that we clean the containers and components and assure containers are closed and only opened in environmentally controlled areas to prevent the introduction of contaminants into the products or components.

Representative samples of each shipment of each lot are collected for testing. Certificates of Analysis (CofA) are reviewed for compliance to pre-established material specifications. If testing is required, the quantity of material and amount required for reserve samples is determined and sampled from incoming containers. Sampling is generally based upon the √N+1 rule for N number of containers unless a higher degree of scrutiny is required. Reserve samples are labeled as to origin (lot number, date received, and expiration date) and stored in a secure, environmentally controlled area.

Testing for compliance with specifications is performed by our in-house ISO 17025-accredited laboratory or an approved contract lab. In the event out-of-specification (OOS) results are found during analysis, we document and investigate through our non-conforming material procedures. Once analysis of the samples is complete, a review and release is performed by our Quality Assurance team.

Material suppliers and their past quality history is tightly monitored through our Supplier Quality program and quality events may result in a Supplier Corrective Action Request (SCAR).

Calculation of Yield (21 CFR 211.103)

This regulation defines the requirements for calculation of yield and requires the manufacturer to know and control how much of the drug product is present in each dosage unit.

Although many colorants and mix ratios of activators and resins are critical in silicone molding processes, traditional device manufacturing processes do not require calculation of yield. To comply with the Pharma calculation of yield requirements, ProMed implemented comprehensive batch records to calculate and document the theoretical yield and actual yield of drug in components that have drug constituent. The batch records are predefined through process development and process validation to assure the specified loading and elution targets are achieved. During manufacturing, calculations are generally performed by one person and independently verified by a second person; when the yield is calculated by automated equipment the result is independently verified by one person.

It is important to note that our combination products typically consist of a molded silicone structure impregnated with the drug substance or active pharmaceutical ingredient (API). Once an active pharmaceutical ingredient is fully encapsulated within a silicone matrix through our molding processes, the next step is to confirm the drugs elution profile and burst. In other words, we test and confirm how fast the drug substance elutes or discharges from the silicone. This complex analytical testing is performed in-house using validated methods or by an approved contract laboratory as appropriate. The results are used to confirm actual yield and that the drug elution profile meets specifications. Conforming product is released for final packaging or further processing by Quality Assurance.

Tamper-Evident Packaging (21 CFR 211.132)

ProMed does not currently engage in manufacturing Over-The-Counter (OTC) drug products and tamper evident packaging is not a requirement in our medical device component manufacturing process. However, in our combination products area, we do use non-resealable pouches and our labeling practices comply with tamper-evident packaging requirements. If those pouches are breached or the labeling is missing, a consumer can reasonably be expected to determine that tampering has occurred.

Expiration Dating (21 CFR 211.137)

Expiration dates for Combination Products with a drug constituent are established through the product development process while working closely with the customer. Expiration date testing and aging studies are established in accordance with the requirements of 21 CFR 211.166 to meet our customers’ requirements. This stability program is managed by ProMed, an approved lab, or our customers. Together, we work to assure the drug product meets applicable standards of identity, strength, quality, and purity at the time of use and label each individual unit for sale with an expiration date as determined by appropriate stability testing.

Testing and Release for Distribution (21 CFR 211.165)

ProMed samples and tests each batch of drug product for conformance to specifications, including the identity and strength of each active ingredient, prior to release. Samples are collected according test plans defined in approved batch records and include the method of sampling and the number of units per batch to be tested.

Samples are tested by our in-house ISO 17025 accredited laboratory or an approved contract lab as required. All test methods used to support conformance to specifications are validated and documented to assure accuracy, sensitivity, specificity and reproducibility where appropriate. For products required to meet microbiological specifications, methods suitability for the product is verified and samples from each lot are tested for compliance prior to release.

ProMed’s Quality Assurance team verifies that the test results conform to predefined acceptance criteria and that the samples and results statistically represent the entire batch prior to approval and release. Any batch failing to meet established standards, specifications, or any other relevant quality control criteria are rejected. Due to the nature of manufacturing molded combination devices, reprocessing is not usually possible, and therefore rejected batches are destroyed.

Stability Testing (21 CFR 211.166)

ProMed’s stability testing practices for Combination Products with a drug constituents are established during the product development process and are specified and managed by our customers.

Special Testing Requirements (21 CFR 211.167)

ProMed tests each batch of drug product purporting to be sterile and/or pyrogen-free using an approved contract laboratory to verify conformance to such requirements prior to product release. The test procedures are included in the approved batch records.

Although ProMed does not manufacture ophthalmic ointments, we do manufacture implantable, drug eluting ophthalmic devices. ProMed ensures that these products have predefined requirements regarding the presence of foreign particles and harsh or abrasive substances and that each batch of product is tested and confirmed to meet these specifications.

Because many molded combination devices are formulated for controlled or extended release, drug burst and elution profiles are critical to product performance. To confirm how fast the drug substance elutes or discharges from the matrix, analytical methods for dissolution and quantification are validated and performed in-house or by an approved contract laboratory.

Reserve Samples (21 CFR 211.170)

ProMed retains an appropriately identified reserve sample from each lot in each shipment of active ingredient or released product. The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether it meets established specifications, except for sterility and pyrogen testing. Reserve samples are retained for all drug product samples and excipients for one year after the drug product expiration dates at ProMed Pharma or at customer site.

Reserve samples are stored in a product-suitable environment in a closed container. The reserve samples are scheduled through our PM system for visual examination at least once a year to ensure that the sample integrity is maintained.

Other Requirements

ProMed implemented a formal procedure for performing Annual Product Quality Reviews (APQR) for each drug product we manufacture at the end of the first year of a product’s commercial manufacturing and every year thereafter. All manufacturing process parameters, failed batches, OOS, non-conformances, complaints or other quality related events are evaluated for trends, systemic issues, or opportunities for improvement. As a contract manufacturer, the report is shared with the customer and any changes are evaluated, validated, and approved by the customer prior to implementation.

Drug products in high concentration areas, such as compounding areas, may pose a threat to our employees’ health and safety. ProMed implemented a program for assessing our personnel’s overall health and the protection and safety features required to keep them safe. To prevent exposure, we perform a risk analysis for each API and specify appropriate containment using appropriate isolators and closed systems. This equipment is then verified to provide appropriate containment as part of our validation program to assure that these safety features are effective to meet our safety standards.


Over the past several years, our Quality Management Systems and management team have matured as we engaged with many new and exciting customers. We have developed expertise in Combination Products including drug-eluting vaginal rings, glaucoma treatments, and diabetes monitoring systems. Our knowledge and experience has added great value to our customers; from the planning stages through regulatory submissions and sustainable manufacturing. ProMed Pharma is positioned to ease your burden and shorten the time required for market launch.